Pyrazole compounds and method for making and using the compounds

ABSTRACT

Disclosed embodiments concern novel interleukin receptor associated kinases (IRAK) inhibitors and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/136,508, filed on Apr. 22, 2016, which claims the benefit of U.S.Provisional Application No. 62/151,274, filed on Apr. 22, 2015, both ofwhich are incorporated herein in their entireties by reference.

FIELD

This disclosure concerns pyrazole compounds, and embodiments of a methodfor making and using the compounds, such as for inhibiting interleukinreceptor-associated kinase (IRAK), and for treating diseases andconditions related to IRAK.

BACKGROUND

Interleukin-1 receptor-associated kinases (IRAKs) are importantmediators of signaling processes, such as toll-like receptors (TLR) andinterleukin-1 receptor (IL-1R) signaling processes. IRAKs have beenimplicated in modulating signaling networks that control inflammation,apoptosis, and cellular differentiation. Four IRAK genes have beenidentified in the human genome (IRAK1, IRAK2, IRAK3 and IRAK4), andstudies have revealed distinct, non-redundant biological roles. IRAK1and IRAK4 have been shown to exhibit kinase activity.

SUMMARY

Disclosed herein are pyrazole compounds, and compositions comprisingsuch compounds that are useful as, inter alia, kinase inhibitors, suchas IRAK inhibitors. Certain disclosed embodiments concern pyrazolecompounds having a formula

or salt, solvate, N-oxide or prodrug thereof, wherein R is aliphatic,heteroaliphatic, heteroaryl, aryl, halo, amide or CN; R¹ is H, aliphaticor heteroaliphatic; or R and R¹, together with the atoms to which theyare attached, form a heterocyclyl ring; R² is H, aliphatic,heteroaliphatic, heterocycloaliphatic, aryl, amide, heterocyclyl oraraliphatic; each R³ independently is H, aliphatic, halogen,heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic,—O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl,amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl,alkylphosphate, or alkylphosphonate; y is from 1 to the number ofpossible substituents on the particular system in question; and Het-1 isheteroaryl. In some embodiments, R is alkyl, amide, heteroaryl, or CN.

In certain embodiments, the compound has a formula

wherein x is from 1 to the number of possible substituents on theparticular system in question, and Het-2 is heteroaryl.

In some embodiments, Het-1 and Het-2, if present, independently is a 5-or 6-membered heteroaryl, and maybe selected from furan, thiophene,pyrazole, pyrrole, imidazole, oxazole, thiazole, isoxazole, isothiazole,1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrazole,pyrimidine, pyridine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine,pyrazine, or pyridazine. In particular embodiments, Het-1 is furan,thiazole or oxazole. In other embodiments, Het-2 is pyridine,pyrimidine, pyrazine, oxadiazole or thiazole.

In some embodiments, the compound has a formula

where Het-3 is a heterocycle, and z is from 1 to the number of possiblesubstituents on the particular system in question. Het-3 may be a 5- or6-membered heteroaryl, and in some embodiments Het-3 is selected fromfuran, thiophene, pyrazole, pyrrole, imidazole, oxazole, thiazole,isoxazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole,1,2,5-thiadiazole or tetrazole. In particular embodiments, Het-3 ispyrazole.

The compound may have a formula selected from

With respect to these formulas, R⁴, R⁵, R⁶ and R⁷ are each independentlyH, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic,—O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl,carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl orsulfinyl. In some examples the compound has a formula

In certain embodiments, the compound has a formula selected from

With respect to these formulas, R⁸, R⁹ and R¹⁰ are each independently H,aliphatic, heteroaliphatic, aryl, —O-aliphatic, araliphatic,heterocyclyl, sulfonyl, nitro, OH, halogen, haloalkyl, carboxyl ester,cyano, acyl, amino, alkyl phosphate or alkylphosphonate, and R¹¹, R¹²,R¹³ and R¹⁴ are each independently H, aliphatic, heteroaliphatic, aryl,heterocyclyl, sulfonyl, nitro, carboxyl ester, cyano or amino.

In particular embodiments, the compound has a formula selected from

where Het-3 is heteroaryl, and in some embodiments,

In particular embodiments of the above formulas, R⁸, R⁹, R¹¹, R¹², R¹³and R¹⁴ are each independently H or alkyl, and R¹⁰ is H, alkyl, carboxylester, acyl, alkyl phosphate, alkyl phosphonate, heterocycloalkyl oraralkyl.

In any of the above formulas, R⁴, R⁵, R⁶ and R⁷ may be eachindependently H, halogen, haloalkyl, aliphatic, heteroaliphatic, alkoxy,heterocyclyl or —O-heterocyclyl. In certain examples, R⁵ is H, halogen,haloaklyl, alkoxy, —O-heterocyclyl or heterocyclyl, and in particularexamples, R⁵ is H, F, CF₃, methoxy, morpholin-4-yl,1-methylpiperidin-4-yl, —O—CH₂C(CH₃)₂OH, or —O-(oxetan-3-yl). In certainexamples, each of R⁴, R⁶ and R⁷ independently is H, CF₃, F.

R² may be H, amide, alkyl, particularly lower alkyl, cycloalkyl,heteroaliphatic, heteroalicyclyl or haloalkyl, and/or may comprisecyclobutyl, azetidinyl, morpholinyl, 4-methylpiperazinyl, oxetanyl,tetrahydrofuranyl, or tetrahydropyranyl. In certain embodiments, R² isH, methyl, difluoromethyl, trifluoroethyl, isopropyl, tetrahydropyranyl,tetrahydrofuranyl, oxetanyl, N-tert-butyloxycarbonyl azetidin-3-yl,3-methyoxy cyclobutyl, 3-benzyloxycyclobutyl, 3-ethyloxy cyclobutyl,3-isopropyl cyclobutyl, 3-hydroxy cyclobutyl, 4-ethoxy cyclohexyl,4-hydroxy cyclohexyl, 4-((2,2-difluoroethyl)amino)cyclohexyl, 3-ethyloxycyclopentyl, or 3-hydroxy cyclopentyl. And in some examples, R¹⁰ is H,alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate oraralkyl. In certain embodiments R¹ is R^(a), —(CR^(a)R^(a))_(m)—O—R^(a),—(CH₂)_(m)—O—R^(a), —(CR^(a)R^(a))_(m)—O—(CR^(a)R^(a))_(m)—O—R^(a) or—(CH₂)_(m)—O—(CH₂)_(m)—O—R^(a); each m independently is 1, 2 or 3; R² isR^(a), R^(b), R^(a) substituted with 1, 2 or 3 R^(b), R^(a) substitutedwith R_(b) and R^(c), R^(a) substituted with R^(c),—(CR^(a)R^(a))_(n)—R^(a), —(CH₂)_(n)—R^(a), —(CR^(a)R^(a))_(n)—R^(b) or—(CH₂)_(n)—R^(b); each of R⁴, R⁵, R⁶ and R⁷ independently is R^(a),R^(b), R^(a) substituted with R^(c), —OR^(a),—O—(CR^(a)R^(a))_(p)—R^(b); R¹⁰ is R^(a), R^(b), R^(a) substituted with—OP(O)(R^(f))₂, R^(a) substituted with 1, 2 or 3 R^(b), R^(a)substituted with R^(c), R^(a) substituted with —P(O)(R^(f))₂, aralkyl,—(CR^(a)R^(a))_(n)—R^(a), —(CH₂)_(n)—R^(a) or —C(O)C(R^(a))₂NR^(a)R^(b);n is 1, 2 or 3; p is 1, 2, or 3; R^(a) is independently for eachoccurrence H, D, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, orC₃₋₆heteroalicyclyl; R^(b) is independently for each occurrence —OH,—CF₃, —OR^(c), —NR^(d)R^(d), —C(O)OH, —C(O)R^(c), —C(O)OR^(c),—C(O)NR^(d)R^(d) or halogen; R^(c) is independently for each occurrenceC₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆heteroalicyclyl, aralkyl, C₁₋₆alkylsubstituted with 1, 2 or 3 R^(e), C₃₋₆cycloalkyl substituted with 1, 2or 3 R^(e), or C₃₋₆heteroalicyclyl substituted with 1, 2 or 3 R^(e);R^(d) is independently for each occurrence H, C₁₋₆alkyl optionallysubstituted with 1, 2 or 3 R^(e), C₃₋₆cycloalkyl optionally substitutedwith 1, 2 or 3 R^(e), or two R^(d) groups together with the nitrogenbound thereto form a C₃₋₆heteroalicyclyl moiety optionally substitutedwith C₁₋₆alkyl, such as morpholinyl, piperidinyl, N-methylpiperidinyl orpyrrolidinyl; R^(e) is independently for each occurrence halogen,C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆heteroalicyclyl, C₆alkyl-OH, —OR^(a),—OC(O)R^(a) or —O-aralkyl; R^(f) is independently for each occurrence—OR^(a), —O⁻M⁺ or —O⁻[M²⁺]_(0.5); each M⁺ independently is an alkalimetal ion or an ammonium ion; and M²⁺ is an alkaline metal earth ion.

In particular embodiments, R² is CH₃OCH₂CH₂—, CH₃OCH₂CH₂OCH₂CH₂—,CH₃CH₂OCH₂CH₂—, methyl, 4-pyranyl, F, CF₃, or H, R³ is H, and/or R⁴, R⁵,R⁶ and R⁷ independently are H, F, or CF₃.

In any of the above embodiments, the compound may be a salt, such as apharmaceutically acceptable acid addition salt or a pharmaceuticallyacceptable base addition salt. In certain examples, the compound is ahydrochloride, formic acid or trifluoroacetic acid salt. In otherexamples, the compound is a sodium, calcium, ammonium, trimethylamine,tris(hydroxymethyl)aminomethane, lysine, arginine, or potassium salt.

Also disclosed herein are embodiments of a composition comprising adisclosed compound and a pharmaceutically acceptable excipient. Thecomposition may also comprise an additional therapeutic agent.Alternatively, the pyrazole compounds, or compositions comprising thepyrazole compounds, may be administered as a combination with a secondtherapeutic(s).

Embodiments of a method for administering a pyrazole compound orcomposition comprising a pyrazole compound(s) are also disclosed. Forexample, disclosed herein are embodiments of a method for treatingdifferent classes of diseases, such as by inhibiting an enzyme, such asa kinase, for example an IRAK protein comprising contacting the IRAKprotein with an effective amount of a pyrazole compound. In someembodiments the method comprises contacting the protein in vitro. Inother embodiments, the IRAK protein may be in a subject. Exemplarycompounds may have an EC₅₀ of from greater than 0 to 5 μM, such as fromgreater than 0 to 1 μM. In certain embodiments, the method comprisesadministering to a subject in need thereof a therapeutically effectiveamount of a pyrazole compound or composition comprising the pyrazolecompound. The method may be a method of treating a disease or conditionfor which an IRAK modulator or inhibitor is indicated.

The foregoing and other objects, features, and advantages of theinvention will become more apparent from the following detaileddescription.

DETAILED DESCRIPTION I. Definitions

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. The singular forms“a,” “an,” and “the” refer to one or more than one, unless the contextclearly dictates otherwise. The term “or” refers to a single element ofstated alternative elements or a combination of two or more elements,unless the context clearly indicates otherwise. As used herein,“comprises” means “includes.” Thus, “comprising A or B,” means“including A, B, or A and B,” without excluding additional elements. Allreferences, including patents and patent applications cited herein, areincorporated by reference.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, percentages, temperatures, times, and soforth, as used in the specification or claims are to be understood asbeing modified by the term “about.” Accordingly, unless otherwiseindicated, implicitly or explicitly, the numerical parameters set forthare approximations that may depend on the desired properties soughtand/or limits of detection under standard test conditions/methods. Whendirectly and explicitly distinguishing embodiments from discussed priorart, the embodiment numbers are not approximates unless the word “about”is recited.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to include hydrogen so thateach carbon conforms to a valence of four. For example, in the structureon the left-hand side of the schematic below there are nine hydrogenatoms implied. The nine hydrogen atoms are depicted in the right-handstructure.

Sometimes a particular atom in a structure is described in textualformula as having a hydrogen or hydrogen atoms, for example —CH₂CH₂—. Itwill be understood by a person of ordinary skill in the art that theaforementioned descriptive techniques are common in the chemical arts toprovide brevity and simplicity to description of organic structures.

A person of ordinary skill in the art will appreciate that thedefinitions may be combined to further describe a particular compound.For example, hydroxyaliphatic refers to an aliphatic group substitutedwith an hydroxy (—OH) group, and haloalkylaryl refers to an aryl groupsubstituted with an alkyl group, where the alkyl group too issubstituted with a halogen, and where the point of attachment to theparent structure is via the aryl moiety since aryl is the base name ofthe substituent.

As used herein, the term “substituted” refers to all subsequentmodifiers in a term, for example in the term “substitutedarylC₁₋₈alkyl,” substitution may occur on the “C₁₋₈alkyl” portion, the“aryl” portion or both portions of the arylC₁₋₈alkyl group. Also by wayof example, alkyl includes substituted cycloalkyl groups.

“Substituted,” when used to modify a specified group or moiety, meansthat at least one, and perhaps two or more, hydrogen atoms of thespecified group or moiety is independently replaced with the same ordifferent substituent groups as defined below. In a particularembodiment, a group, moiety or substituent may be substituted orunsubstituted, unless expressly defined as either “unsubstituted” or“substituted.” Accordingly, any of the groups specified herein may beunsubstituted or substituted. In particular embodiments, the substituentmay or may not be expressly defined as substituted, but is stillcontemplated to be optionally substituted. For example, an “alkyl”substituent may be unsubstituted or substituted, but an “unsubstitutedalkyl” may not be substituted.

“Substituents” or “substituent groups” for substituting for one or morehydrogen atoms on saturated carbon atoms in the specified group ormoiety are, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—N(R⁸⁰)₂, haloalkyl, perhaloalkyl, —CN, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₃⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(O⁻)₂M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)N(R⁸⁰)₂, —C(NR⁷⁰)(R⁸⁰)₂,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰ isC₁₋₆alkyl optionally substituted with 1, 2, or 3 OH; each R⁷⁰ isindependently for each occurrence hydrogen or R⁶⁰; each R⁸⁰ isindependently for each occurrence R⁷⁰ or alternatively, two R⁸⁰ groups,taken together with the nitrogen atom to which they are bonded, form a3- to 7-membered heteroalicyclyl which optionally includes from 1 to 4of the same or different additional heteroatoms selected from O, N andS, of which N optionally has H or C₁-C₃alkyl substitution; and each M⁺is a counter ion with a net single positive charge. Each M⁺ isindependently for each occurrence, for example, an alkali metal ion,such as K⁺, Na⁺, Li⁺; an ammonium ion, such as +N(R⁶⁰)₄; a protonatedamino acid ion, such as a lysine ion, or an arginine ion; or an alkalinemetal earth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (asubscript “0.5” means, for example, that one of the counter ions forsuch divalent alkali earth ions can be an ionized form of a compound ofthe invention and the other a typical counter ion such as chloride, ortwo ionized compounds can serve as counter ions for such divalent alkaliearth ions, or a doubly ionized compound can serve as the counter ionfor such divalent alkali earth ions). As specific examples, —N(R⁸⁰)₂includes —NH₂, —NH-alkyl, —NH-pyrrolidin-3-yl, N-pyrrolidinyl,N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl and the like. Anytwo hydrogen atoms on a single carbon can be replaced with ═O, ═NR⁷⁰,═N—OR⁷⁰, ═N₂ or ═S.

Substituent groups for replacing hydrogen atoms on unsaturated carbonatoms in groups containing unsaturated carbons are, unless otherwisespecified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂,perhaloalkyl, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺,—SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —PO₃ ⁻²M²⁺,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)N(R⁸⁰)₂, —OC(O)R⁷⁰,—OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂,—NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ areas previously defined, provided that in case of substituted alkene oralkyne, the substituents are not —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, or —S⁻M⁺.

Substituent groups for replacing hydrogen atoms on nitrogen atoms ingroups containing such nitrogen atoms are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂, perhaloalkyl, —CN, —NO,—NO₂, —S(O)₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OS(O)₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰,—PO₃ ²⁻(M⁺)₂, —PO₃ ²⁻M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined.

In one embodiment, a group that is substituted has 1 substituent, 2substituents, substituents, or 4 substituents.

Additionally, in embodiments where a group or moiety is substituted witha substituted substituent, the nesting of such substituted substituentsis limited to three, thereby preventing the formation of polymers. Thus,in a group or moiety comprising a first group that is a substituent on asecond group that is itself a substituent on a third group, which isattached to the parent structure, the first (outermost) group can onlybe substituted with unsubstituted substituents. For example, in a groupcomprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substitutedwith substituents that are not themselves substituted.

“Acyl” refers to the group —C(O)R, where R is H, aliphatic,heteroaliphatic, heterocyclic or aryl. Exemplary acyl moieties include,but are not limited to, —C(O)H, —C(O)alkyl, —C(O)C₁-C₆alkyl,—C(O)C₁-C₆haloalkyl-C(O)cycloalkyl, —C(O)alkenyl, —C(O)cycloalkenyl,—C(O)aryl, —C(O)heteroaryl, or —C(O)heterocyclyl. Specific examplesinclude, —C(O)H, —C(O)Me, —C(O)Et, or —C(O)cyclopropyl.

“Aliphatic” refers to a substantially hydrocarbon-based group or moiety,including alkyl, alkenyl, alkynyl groups, cyclic versions thereof, suchas cycloalkyl, cycloalkenyl or cycloalkynyl, and further includingstraight- and branched-chain arrangements, and all stereo and positionisomers as well. Unless expressly stated otherwise, an aliphatic groupcontains from one to twenty-five carbon atoms; for example, from one tofifteen, from one to ten, from one to six, or from one to four carbonatoms.

“Lower aliphatic” refers to an aliphatic group containing from one toten carbon atoms. An aliphatic group may be substituted orunsubstituted, unless expressly referred to as an “unsubstitutedaliphatic” or a “substituted aliphatic.” An aliphatic group can besubstituted with one or more substituents (up to two substituents foreach methylene carbon in an aliphatic chain, or up to one substituentfor each carbon of a —C═C— double bond in an aliphatic chain, or up toone substituent for a carbon of a terminal methine group). Exemplarysubstituents include, but are not limited to, alkyl, alkenyl, alkynyl,alkoxy, alkylamino, alkylthio, acyl, aldehyde, amide, amino, aminoalkyl,aryl, arylalkyl, carboxyl, cyano, cycloalkyl, dialkylamino, halo,haloaliphatic, heteroaliphatic, heteroaryl, heterocycloaliphatic,hydroxyl, oxo, sulfonamide, sulfhydryl, thioalkoxy, phosphate, or otherfunctionality.

“Alkoxy” refers to the group —OR, where R is a substituted orunsubstituted alkyl group. In certain examples R is a C₁₋₆ alkyl group.Methoxy (—OCH₃) and ethoxy (—OCH₂CH₃) are exemplary alkoxy groups. In asubstituted alkoxy, R is substituted alkyl, examples of which useful inthe presently disclosed compounds include haloalkoxy groups, such as—OCF₂H.

“Alkoxyalkyl” refers to the group -alkyl-OR, where R is a substituted orunsubstituted alkyl group. —CH₂CH₂—O—CH₂CH₃ is an exemplary alkoxyalkylgroup.

“Alkyl” refers to a saturated aliphatic hydrocarbyl group having from 1to 25 carbon atoms, typically 1 to 10 carbon atoms such as 1 to 6 carbonatoms (C₁-C₆alkyl). An alkyl moiety may be substituted or unsubstituted.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃), ethyl (—CH₂CH₃), n-propyl (—CH₂CH₂CH₃),isopropyl (—CH(CH₃)₂), n-butyl (—CH₂CH₂CH₂CH₃), isobutyl(—CH₂CH₂(CH₃)₂), sec-butyl (—CH(CH₃)(CH₂CH₃), t-butyl (—C(CH₃)₃),n-pentyl (—CH₂CH₂CH₂CH₂CH₃), and neopentyl (—CH₂C(CH₃)₃).

“Amino” refers to the group —NH₂, —NHR, or —NRR, where each Rindependently is selected from H, aliphatic, heteroaliphatic, aryl orheterocyclic, or two R groups together with the nitrogen attachedthereto form a heterocyclic ring. Examples of such heterocyclic ringsinclude those wherein two R groups together with the nitrogen to whichthey are attached form a —(CH₂)₂₋₅— ring optionally interrupted by oneor two heteratom groups, such as —O— or —N(R^(g)) such as in the groups

and wherein R^(g) is R⁷⁰, —C(O)R⁷⁰, —C(O)OR⁶⁰ or —C(O)N(R⁸⁰)₂.

“Amide” refers to the group —N(H)acyl, or —C(O)amino.

“Aryl” or “aromatic” refers to an aromatic group of, unless specifiedotherwise, from 5 to 15 ring atoms having a single ring (e.g., phenyl)or multiple fused rings in which at least one ring is aromatic (e.g.,naphthyl). For groups having multiple rings, at least one of which isaromatic and one is not, such groups are nevertheless referred to as“aryl” provided that the point of attachment to the remainder of thecompound is through an atom of an aromatic portion of the aryl group.Aryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic.Unless otherwise stated, an aryl group may be substituted orunsubstituted.

“Araliphatic” refers to an aryl group attached to the parent via analiphatic moiety. Araliphatic includes aralkyl or arylalkyl groups suchas benzyl and phenylethyl.

“Carboxyl,” “carboxy” or “carboxylate” refers to —CO₂H, —C(O)O or saltsthereof.

“Carboxyl ester” or “carboxy ester” refers to the group —C(O)OR, where Ris aliphatic, heteroaliphatic, cyclic, and heterocyclic, including aryland heteroaryl.

“Cyano” refers to the group —CN.

“Cycloaliphatic” refers to a cyclic aliphatic group having a single ring(e.g., cyclohexyl), or multiple rings, such as in a fused, bridged orspirocyclic system, at least one of which is aliphatic, provided thatthe point of attachment is through an atom of an aliphatic region of thecycloaliphatic group. Cycloaliphatic includes saturated and unsaturatedsystems, including cycloalkyl, cycloalkenyl and cycloalkynyl. Exemplarycycloaliphatic groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, orcyclohexenyl.

“Halo,” “halide” or “halogen” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to an alkyl moiety substituted with one or morehalogens. An exemplary haloalkyl moiety is CF₃.

“Heteroaliphatic” refers to an aliphatic compound or group having atleast one heteroatom, i.e., one or more carbon atoms has been replacedwith an atom having at least one lone pair of electrons, typicallynitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphaticcompounds or groups may be substituted or unsubstituted, branched orunbranched, acyclic or cyclic, such as a heteroalicyclyl group, chiralor achiral, and may include heterocycle, heterocyclyl,heterocycloaliphatic, or heterocyclic groups.

“Heteroaryl” refers to an aryl group where one or more carbon atoms,such as methine (—CH═) or vinylene (—CH═CH—) groups, have been replacedby trivalent or divalent heteroatoms, respectively, in such a way as tomaintain aromaticity, such as determined by the continuous, delocalizedπ-electron system characteristic of the aromatic group, and the numberof out of plane π-electrons corresponding to the Hickel rule (4n+2).

“Heterocycloalkyl” and “heterocyclylalkyl” refer to a heterocyclylmoiety attached to the parent structure via an alkyl moiety, forexample, (tetrahydropyran-4-yl)methyl, (pyridine-4-yl)methyl,morpholinoethyl or piperazin-1-ylethyl.

“Heterocyclyl,” “heterocyclo” and “heterocycle” refer to aromatic andnon-aromatic ring systems, and more specifically refer to a stablethree- to fifteen-membered ring moiety comprising carbon atoms and atleast one, such as from one to five heteroatoms. The heterocyclyl moietymay be a monocyclic moiety, or may comprise multiple rings, such as in abicyclic or tricyclic ring system, provided that at least one of therings contains a heteroatom. Such a multiple ring moiety can includefused or bridged ring systems as well as spirocyclic systems; and thenitrogen, phosphorus, carbon, silicon or sulfur atoms in theheterocyclyl moiety can be optionally oxidized to various oxidationstates. For convenience, nitrogens, particularly but not exclusively,those defined as annular aromatic nitrogens, are meant to include theircorresponding N-oxide form, although not explicitly defined as such in aparticular example. Thus, for a compound having, for example, a pyridylring; the corresponding pyridyl-N-oxide is included as another compoundof the invention, unless expressly excluded by context. In addition,annular nitrogen atoms can be optionally quaternized. Heterocycleincludes heteroaryl moieties, and heteroalicyclyl orheterocycloaliphatic moieties, which are heterocyclyl rings which arepartially or fully saturated. Thus a term such as “heterocyclylalkyl”includes heteroalicyclylalkyls and heteroarylalkyls. Examples ofheterocyclyl groups include, but are not limited to, azetidinyl,oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl,carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl,perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl,triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane,diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Hydroxyl” refers to the group —OH.

“Nitro” refers to the group —NO₂.

“Phosphate” refers to the group —O—P(O)(OR′)₂, where each —OR′independently is —OH, —O-aliphatic, such as —O-alkyl, —O-aryl, or—O-aralkyl, or —OR′ is —O⁻M⁺, where M⁺ is a counter ion with a singlepositive charge. Each M⁺ may be an alkali ion, such as K⁺, Na⁺, Li⁺; anammonium ion, such as +N(R″)₄ where R″ is H, aliphatic, heterocyclyl oraryl; or an alkaline earth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or[Ba²⁺]_(0.5). Alkyl phosphate refers to the group -alkyl-phosphate, suchas, for example, —CH₂OP(O)(OH)₂, or a salt thereof, such as —CH₂OP(O)(ONa)₂.

“Phosphonate” refers to the group —P(O)(OR′)₂, where each —OR′independently is —OH, —O-aliphatic such as —O-alkyl, —O-aryl, or—O-aralkyl, or where —OR′ is —O⁻M⁺, and M⁺ is a counter ion with asingle positive charge. Each M⁺ may be an alkali metal ion, such as K⁺,Na⁺, Li⁺; an ammonium ion, such as +N(R″)₄ where R″ is H, aliphatic,heterocyclyl or aryl; or an alkaline earth metal ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Alkyl phosphonate refers tothe group -alkyl-phosphonate, such as, for example, —CH₂P(O)(OH)₂, or—CH₂P(O)(O Na+)₂.

“Patient” or “Subject” refers to mammals and other animals, particularlyhumans. Thus disclosed methods are applicable to both human therapy andveterinary applications.

“Pharmaceutically acceptable excipient” refers to a substance, otherthan the active ingredient, that is included in a formulation of theactive ingredient. As used herein, an excipient may be incorporatedwithin particles of a pharmaceutical composition, or it may bephysically mixed with particles of a pharmaceutical composition. Anexcipient can be used, for example, to dilute an active agent and/or tomodify properties of a pharmaceutical composition. Excipients caninclude, but are not limited to, antiadherents, binders, coatings,enteric coatings, disintegrants, flavorings, sweeteners, colorants,lubricants, glidants, sorbents, preservatives, adjuvants, carriers orvehicles. Excipients may be starches and modified starches, celluloseand cellulose derivatives, saccharides and their derivatives such asdisaccharides, polysaccharides and sugar alcohols, protein, syntheticpolymers, crosslinked polymers, antioxidants, amino acids orpreservatives. Exemplary excipients include, but are not limited to,magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose,starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose,xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP),polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate(also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose,dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitaminC, retinyl palmitate, selenium, cysteine, methionine, citric acid,sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc,magnesium carbonate, sodium starch glycolate, tartrazine, aspartame,benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphiteor lanolin.

An “adjuvant” is an excipient that modifies the effect of other agents,typically the active ingredient. Adjuvants are often pharmacologicaland/or immunological agents. An adjuvant may modify the effect of anactive ingredient by increasing an immune response. An adjuvant may alsoact as a stabilizing agent for a formulation. Exemplary adjuvantsinclude, but are not limited to, aluminum hydroxide, alum, aluminumphosphate, killed bacteria, squalene, detergents, cytokines, paraffinoil, and combination adjuvants, such as freund's complete adjuvant orfreund's incomplete adjuvant.

“Pharmaceutically acceptable carrier” refers to an excipient that is acarrier or vehicle, such as a suspension aid, solubilizing aid, oraerosolization aid. Pharmaceutically acceptable carriers areconventional. Remington: The Science and Practice of Pharmacy, TheUniversity of the Sciences in Philadelphia, Editor, Lippincott,Williams, & Wilkins, Philadelphia, Pa., 21^(st) Edition (2005),describes compositions and formulations suitable for pharmaceuticaldelivery of one or more therapeutic compositions and additionalpharmaceutical agents.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually comprise injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. In some examples, the pharmaceutically acceptable carrier maybe sterile to be suitable for administration to a subject (for example,by parenteral, intramuscular, or subcutaneous injection). In addition tobiologically-neutral carriers, pharmaceutical compositions to beadministered can contain minor amounts of non-toxic auxiliarysubstances, such as wetting or emulsifying agents, preservatives, and pHbuffering agents and the like, for example sodium acetate or sorbitanmonolaurate.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound that are derived from a variety of organic andinorganic counter ions as will be known to a person of ordinary skill inthe art and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate, and the like. “Pharmaceutically acceptable acidaddition salts” are a subset of “pharmaceutically acceptable salts” thatretain the biological effectiveness of the free bases while formed byacid partners. In particular, the disclosed compounds form salts with avariety of pharmaceutically acceptable acids, including, withoutlimitation, inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, as well asorganic acids such as formic acid, acetic acid, trifluoroacetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid,isethionic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, xinafoic acid and the like.“Pharmaceutically acceptable base addition salts” are a subset of“pharmaceutically acceptable salts” that are derived from inorganicbases such as sodium, potassium, lithium, ammonium, calcium, magnesium,iron, zinc, copper, manganese, aluminum salts and the like. Exemplarysalts are the ammonium, potassium, sodium, calcium, and magnesium salts.Salts derived from pharmaceutically acceptable organic bases include,but are not limited to, salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine. (See, for example, S. M.Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19which is incorporated herein by reference.) In particular disclosedembodiments, the pyrazole compound may be a formate or sodium salt.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease, or to ameliorate or eradicate one or more of itssymptoms and/or to prevent the occurrence of the disease or disorder.The amount of a compound which constitutes a “therapeutically effectiveamount” will vary depending on the compound, the disease state and itsseverity, the age of the patient to be treated, and the like. Thetherapeutically effective amount can be determined by a person ofordinary skill in the art.

“Prodrug” refers to compounds that are transformed in vivo to yield abiologically active compound, particularly the parent compound, forexample, by hydrolysis in the gut or enzymatic conversion. Commonexamples of prodrug moieties include, but are not limited to, ester andamide forms of a compound having an active form bearing a carboxylicacid moiety. Examples of pharmaceutically acceptable esters of thecompounds of this invention include, but are not limited to, esters ofphosphate groups and carboxylic acids, such as aliphatic esters,particularly alkyl esters (for example C₁₋₆alkyl esters). Other prodrugmoieties include phosphate esters, such as —CH₂—O—P(O)(OR′)₂ or a saltthereof, wherein R′ is H or C₁₋₆alkyl.

Acceptable esters also include cycloalkyl esters and arylalkyl esterssuch as, but not limited to benzyl. Examples of pharmaceuticallyacceptable amides of the compounds of this invention include, but arenot limited to, primary amides, and secondary and tertiary alkyl amides(for example with between about one and about six carbons). Amides andesters of disclosed exemplary embodiments of compounds according to thepresent invention can be prepared according to conventional methods. Athorough discussion of prodrugs is provided in T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S. SymposiumSeries, and in Bioreversible Carriers in Drug Design, ed. Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987,both of which are incorporated herein by reference for all purposes.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.The compounds described herein can exist in un-solvated as well assolvated forms when combined with solvents, pharmaceutically acceptableor not, such as water, ethanol, and the like. Solvated forms of thepresently disclosed compounds are within the scope of the embodimentsdisclosed herein.

“Sulfonamide” refers to the group or moiety —SO₂amino, or—N(R^(c))sulfonyl, where R^(c) is H, aliphatic, heteroaliphatic, cyclic,and heterocyclic, including aryl and heteroaryl.

“Sulfanyl” refers to the group or —SH, —S-aliphatic, —S-heteroaliphatic,—S-cyclic, —S— heterocyclyl, including —S-aryl and —S-heteroaryl.

“Sulfinyl” refers to the group or moiety —S(O)H, —S(O)aliphatic,—S(O)heteroaliphatic, —S(O)cyclic, —S(O)heterocyclyl, including—S(O)aryl and —S(O)heteroaryl.

“Sulfonyl” refers to the group: —SO₂H, —SO₂aliphatic,—SO₂heteroaliphatic, —SO₂cyclic, —SO₂heterocyclyl, including —SO₂aryland —SO₂heteroaryl.

“Treating” or “treatment” as used herein concerns treatment of a diseaseor condition of interest in a patient or subject, particularly a humanhaving the disease or condition of interest, and includes by way ofexample, and without limitation:

(i) preventing the disease or condition from occurring in a patient orsubject, in particular, when such patient or subject is predisposed tothe condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, for example, arresting orslowing its development;

(iii) relieving the disease or condition, for example, causingregression of the disease or condition or a symptom thereof; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” can be usedinterchangeably or can be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been determined) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, where a more or lessspecific set of symptoms have been identified by clinicians.

The above definitions and the following general formulas are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluoro groups). Such impermissible substitutionpatterns are easily recognized by a person having ordinary skill in theart.

Any of the groups referred to herein may be optionally substituted by atleast one, possibly two or more, substituents as defined herein. Thatis, a substituted group has at least one, possible two or more,substitutable hydrogens replaced by a substituent or substitutents asdefined herein, unless the context indicates otherwise or a particularstructural formula precludes substitution.

A person of ordinary skill in the art will appreciate that compounds mayexhibit the phenomena of tautomerism, conformational isomerism,geometric isomerism, and/or optical isomerism. For example, certaindisclosed compounds can include one or more chiral centers and/or doublebonds and as a consequence can exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers,diasteromers, and mixtures thereof, such as racemic mixtures. As anotherexample, certain disclosed compounds can exist in several tautomericforms, including the enol form, the keto form, and mixtures thereof. Asthe various compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric, or geometricisomeric forms, it would be understood that the disclosed compoundsencompass any tautomeric, conformational isomeric, optical isomeric,and/or geometric isomeric forms of the compounds described herein, aswell as mixtures of these various different isomeric forms. In cases oflimited rotation, e.g. around the amide bond or between two directlyattached rings such as the pyrazole and pryidyl rings, atropisomers arealso possible and are also specifically included in the compounds of theinvention.

In any embodiments, any or all hydrogens present in the compound, or ina particular group or moiety within the compound, may be replaced by adeuterium or a tritium. Thus, a recitation of alkyl includes deuteratedalkyl, where from one to the maximum number of hydrogens present may bereplaced by deuterium. For example, ethyl may be C₂H₅ or C₂H₅ where from1 to 5 hydrogens are replaced by deuterium.

II. IRAK-Active Compounds and Compositions Comprising IRAK-ActiveCompounds

A. Pyrazoles

Disclosed herein are pyrazole compounds, methods of making thecompounds, and methods of using the compounds. In one embodiment thedisclosed compounds are tyrosine kinase inhibitors. In a particularembodiment the compounds useful in blocking one or more cytokinesignaling pathways, such as the IL-17 signaling pathway. For certainembodiments, the pyrazole compounds are useful for treating conditionsin which inhibition of an interleukin-1 receptor-associated kinase(IRAK) pathway is therapeutically useful. In some embodiments, thecompounds directly inhibit an IRAK protein, such as IRAK1, IRAK2, IRAK3or IRAK4.

Exemplary pyrazole compounds within the scope of the present inventionhave a general formula 1

or salts, prodrugs, N-oxides or solvates thereof, wherein the compoundsare not a compound disclosed in WO 2011/043371. With reference toformula 1, R is aliphatic, including alkyl; heteroaliphatic; heteroaryl;aryl; CN; halo; or amide. In some embodiments, R is alkyl, particularlyCF₃, heteroaryl, amide or CN. R¹ is H, aliphatic or heteroaliphatic.Alternatively, R and R¹, together with the atoms to which they areattached, form a ring, such as a heterocyclyl ring, having 3, 4, 5, 6,7, 8 or more ring atoms, particularly 5, 6, or 7 ring atoms. Het-1 isheteroaryl, and may comprise a single ring or multiple rings, such as ina fused ring system. R² is H; aliphatic, including alkyl, alkenyl,alkynyl, cycloalkyl, and cycloalkenyl; heteroaliphatic; heterocyclyl,including heteroaryl and heterocycloaliphatic; amide; aryl; oraraliphatic. y is from 1 to the number of possible substituents on theparticular system in question, such as from 1 to 2, 3, 4, 5, or at least6. Each R³ independently is H; aliphatic, including alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; halogen;heteroaliphatic; —O-aliphatic, such as alkoxy; heterocyclyl, includingheteroaryl and heterocycloaliphatic; aryl; araliphatic; —O—heterocyclyl; hydroxyl; nitro; cyano; carboxyl; carboxyl ester; acyl;amide; amino; sulfonyl; sulfonamide; sulfanyl; sulfinyl; haloalkyl;alkylphosphate; or alkylphosphonate. Het-1 can be unsubstituted (if R³is H for all occurrences on that particular moiety) or substituted. Insome embodiments of formula I, R³ is not pyridinyl. In otherembodiments, R³ is not pyridinyl, thiophenyl, furyl, pyrazinyl,quinolinyl, or pyrrolopyridinyl.

For certain embodiments of formula 1, Het-1 may be a 5- or 6-memberedheteroaryl. In some embodiments, Het-1 is a 5-membered heteroaryl ring.In particular examples, Het-1 is furan; thiophene; pyrazole; pyrrole;imidazole; oxazole; thiazole; isoxazole; isothiazole; triazole, such as1,2,3-triazole, 1,2,4-triazole, or 1,3,4-triazole; oxadiazole, such as1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, or1,2,5-oxadiazole; thiadiazole, such as 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, or 1,2,5-thiadiazole; ortetrazole. In particular examples, Het-1 is furan, thiazole or oxazole,such as furan-2-yl, furan-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl or oxazol-5-yl.

In some embodiments of formula 1, R² is H, alkyl, cycloaliphatic,typically cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, heteroaliphatic, or heterocycloaliphatic. In some examples,R² may be substituted with a hydroxyl group.

In some embodiments, R¹ is R^(a), —(CR^(a)R^(a))_(m)—O—R^(a),—(CH₂)_(m)—O—R^(a), —(CR^(a)R^(a))_(m)—O—(CR^(a)R^(a))_(m)—O—R^(a),—[(CH₂)_(m)—O—]_(n)—R^(a) or —(CH₂)_(m)—O—(CH₂)_(m)—O—R^(a) wherein eachm and n independently are 1, 2 or 3;

R² is R^(a), R^(b), R^(a) substituted with 1, 2, or 3 R^(b), R^(a)substituted with R^(b) and R^(c), R^(a) substituted with R^(c),—(CR^(a)R^(a))_(n)—R^(a), —(CH₂)_(n)—R^(a), —(CR^(a)R^(a))_(n)—R^(b),—(CH₂)_(n)—R^(b), —[(CH₂)_(m)—O—]_(n)—R^(a), [(CH₂)_(m)—O-]_(n)-[R^(a)substituted with 1, 2 or 3 R^(b)], or —(CH₂)_(m)—O—(CH₂)_(m)—O—R^(a)wherein each m and n independently are 1, 2 or 3;

R^(a) is independently for each occurrence H, D, C₁₋₆alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl or C₃₋₆heteroalicyclyl;

R^(b) is independently for each occurrence —OH, —CF₃, —OR^(c),—NR^(d)R^(d), —C(O)OH, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(d)R^(d) orhalogen;

R^(c) is independently for each occurrence C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆heteroalicyclyl, aralkyl, C₁₋₆alkyl substituted with 1, 2 or 3R^(e), C₃₋₆cycloalkyl substituted with 1, 2 or 3 R^(e), orC₃₋₆heteroalicyclyl substituted with 1, 2 or 3 R^(e);

R^(d) is independently for each occurrence H, C₁₋₆alkyl optionallysubstituted with 1, 2 or 3 R^(e), C₃₋₆cycloalkyl optionally substitutedwith 1, 2 or 3 R^(e), or two R^(d) groups together with the nitrogenbound thereto form a C₃₋₆heteroalicyclyl moiety optionally substitutedwith C₁₋₆alkyl and optionally interrupted with one or two —O— or—N(R^(g)) wherein R^(g) is R⁷⁰, —C(O)R⁷⁰, —C(O)OR⁶⁰ or —C(O)N(R⁸⁰)₂; and

R^(e) is independently for each occurrence halogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, C₃₋₆heteroalicyclyl, C₁₋₆alkyl-OH, —OR^(a), —OC(O)R^(a)or —O-aralkyl.

With respect to formula 1, Het-1 may be: 1A) a 5-membered heteroaryl;1B) a 6-membered heteroaryl; 1C) selected from furan, thiazole, oroxazole; 1D) furan; 1E) oxazole; 1F) thiazole; 1G) furan-2-yl; 1H)furan-2-yl substituted at least at the 5-position; 1I) furan-2-ylsubstituted at least at the 5-position with a heteroaryl moiety; 1J)oxazol-4-yl; 1K) oxazol-4-yl substituted at least at the 2-position; 1L)oxazol-4-yl substituted at least at the 2-position with a heteroarylmoiety; 1M) 2-(pyrazol-4-yl)oxazol-4-yl; 1N)2-((1-cyclopropylmethyl)pyrazol-4-yl)oxazol-4-yl; 10) thiazol-4-yl; 1P)thiazol-4-yl substituted at least at the 2-position; or 1Q) thiazol-4-ylsubstituted at least at the 2-position with a heteroaryl moiety.

With respect to Het-1 embodiments 1A to 1Q, R may be, in combinationwith 1A to 1Q: 2A) heteroaryl; 2B) aliphatic; 2C) a 5-memberedheteroaryl; 2D) a 6-membered heteroaryl; 2E) an alkyl; 2F) amide; 2G)—CF₃; 2G) —CN; 2H) —C(O)NH₂; 2I) selected from pyridine, thiazole,oxadiazole, pyrazine, or pyrimidine; 2J) thiazol-2-yl; 2K)pyrimidin-2-yl; 2L) pyridin-2-yl; 2M) pyrazine-2-yl; 2N) oxadiazol-2-yl;20) 5-morpholinylpyridin-2-yl; 2P)5-(N-methylpiperidin-1-yl)pyridine-2-yl; 2Q)5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl; 2R)5-(oxetan-3-yloxy)pyridin-2-yl; 2S) 5-methoxypyridin-2-yl; 2T)3-fluoropyrid-2-yl; 2U) 1,3,4-oxadiazol-2-yl; 2V)5-trifluoromethylpyridin-2-yl; 2W) 3-trifluoromethylpyridin-2-yl; 2X)6-trifluoromethylpyridin-2-yl; 2Y) 5-fluoropyrid-2-yl; 2Z)4-fluoropyrid-2-yl; or 2AA) 6-fluoropyrid-2-yl;3,6-difluoropyridin-2-yl.

A person of ordinary skill in the art will understand that any of 2A to2AA may be combined with any of 1A to 1Q, to form any and allcombinations between such substituents.

With respect to the Het-1 embodiments 1A to 1Q and the R embodiments 2Ato 2AB, R¹ is, in combination with 1A to 1Q and 2A to 2AA: 3A)aliphatic; 3B) heteroaliphatic; 3C) H; or 3D) —CH₂CH₂OCH₂CH₂OCH₃.

Alternatively, with respect to the Het-1 embodiments 1A to 1Q, R and R¹together form combined embodiment 3E) a 6-membered heterocyclyl ringthat comprises the atoms to which R and R¹ are attached.

A person of ordinary skill in the art will understand that any of 3A to3E may be combined with any of 1A to 1Q, and any of 2A to 2AA, whereappropriate, to form any and all combinations between such substituents.

With respect to the Het-1 embodiments 1A to 1Q, the R embodiments 2A to2AA and the R¹ embodiments 3A to 3D, or the combined R and R¹ embodiment3E, R² may be, in any combination with 1A to 1Q, and 2A to 2AA and 3A to3D, or 3E: 4A) H, aliphatic, heteroaliphatic, heterocyclyl, aryl, amideor araliphatic; 4B) H, alkyl, cycloalkyl, cycloalkenyl orheterocycloaliphatic; 4C) heterocycloaliphatic; 4D) alkyl; 4E)cycloalkyl substituted with O-alkyl, N(alkyl)₂, OH, halogen,heterocyclyl, or a combination thereof; 4F) tetrahydropyran, oxetane,tetrahydrofuran or azetidine; 4G) cyclobutyl, cyclopentyl, cyclohexyl,or cyclobutenyl; 4H) —C₁₋₆alkyl-O—C₁₋₆alkyl or—C₁₋₆alkyl-O—C₁₋₆alkyl-O—C₁₋₆alkyl; 41) —CH₂CH₂OCH₂CH₂OCH₃; 4J)—CH₂CH₂OCH₂CH₃; 4K) —CH₂CH₂OCH₂CH₂F; 4L) —CH₂CH₂OCH₂CHF₂; 4M)—CH₂CH₂OCH₂CF₃; 4N) H; 40) CH₂C(CH₃)₂OH; 4P) CH₂CH₂OCH₃; 4Q) CH₂CH₂OH;4R) —CH₂CF₃; 4S) —CHF₂; 4T) —CH₂CH(OH)CF₃; 4U) —CH₂(OH)(CF₃)₂; 4V)—C(O)N(CH₃)₂; 4W) —C(O)N(Et)₂; 4X) —C(O)-morpholine; 4Y) benzyl; 4Z)3-fluorocyclobut-2-en-1-yl; 4AA) 3,3-difluorocyclobut-1-yl; 4AB)tetrahydropyran-4-yl; 4AC) oxetan-3-yl; 4AD) (1r,3r)-3-ethoxycyclobutyl; 4AE) (1s, 3s)-3-ethoxycyclobutyl; 4AF) (1s,3s)-3-hydroxycyclobutyl; 4AG) (1r, 3r)-3-hydroxycyclobutyl; 4AH) (1s,3s)-3-dimethylaminocyclobutyl; 4AI) (1r, 3r)-3-dimethylaminocyclobutyl;4AJ) (3-methyloxetan-3-yl)methyl; 4AK) methyl; 4AL)1-(tert-butoxycarbonyl)azetidin-3-yl; 4AM) 3-methoxycyclobutyl; 4AN)(1r, 3r)-3-methoxycyclobutyl; 4AO) (1s, 3s)-3-methoxycyclobutyl; 4AP)3-benzyloxycyclobutyl; 4AQ) azetidin-3-yl; 4AR) 1-acetoxyazetidin-3-yl;4AS) 1-(tert-butylcarbamoyl)azetidin-3-yl; 4AT)1-(propylcarbamoyl)azetidin-3-yl; 4AU)1-(cyclopropylcarbamoyl)azetidin-3-yl; 4AV)1-(cyclopropanecarbonyl)azetidin-3-yl; 4AW)1-(tert-butylcarbonyl)azetidin-3-yl; 4AX)1-(pyrrolidine-1-carbonyl)azetidin-3-yl; 4AY)1-(isopropanecarbonyl)azetidin-3-yl; 4AZ)1-(2,2,2-trifluoroethyl)azetidin-3-yl; 4BA) 1-methylazetidin-3-yl; 4BB)1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl; 4BC) isopropyl;4BD) 2-morpholinoethyl; 4BE) (4-methylpiperazin-1-yl)ethyl; 4BF)tetrahydropyran-3-yl; 4BG) (tetrahydropyran-4-yl)methyl; 4BH)(3-(hydroxymethyl)oxetan-3-yl)methyl; 4BI) 2-(diethylamino)ethyl; 4BJ)2-fluoroethyl; 4BK) (1R, 3R)-3-hydroxycyclopentyl; 4BL) (1R,3S)-3-hydroxycyclopentyl; 4BM) (1S, 3R)-3-hydroxycyclopentyl; 4BN) (1S,3S)-3-hydroxycyclopentyl; 4B0) 1,4-dioxaspiro[4,5]decan-8-yl; 4BP) (1s,3s)-3-(2-fluoroethoxy)cyclobutyl; 4BQ) (1r,3r)-3-(2-fluoroethoxy)cyclobutyl; 4BR) (Is,3s)-3-(2-trifloroethoxy)cyclobutyl; 4BS) (1r,3r)-3-(2-trifloroethoxy)cyclobutyl; 4BT) (1s,3s)-3-isopropoxycyclobutyl; 4BU) (1r, 3r)-3-isopropoxycyclobutyl; 4BV)(1r, 3r)-3-hydroxy-3-methylcyclobutyl; 4BW) (1s,3s)-3-hydroxy-3-methylcyclobutyl; 4BX) (1s, 3s)-3-ethoxy-d₅)cyclobutyl;4BY) (1r, 3r)-3-ethoxy-d₅)cyclobutyl; 4BZ) (1R, 3R)-3-ethoxycyclopentyl;4CA) (1R, 3S)-3-ethoxycyclopentyl; 4CB) (1S, 3R)-3-ethoxycyclopentyl;4CC) (1S, 3S)-3-ethoxycyclopentyl; 4CD) (1R, 3R)-3-hydroxycyclohexyl;4CE) (1S, 3S)-3-hydroxycyclohexyl; 4CF) (1R, 3R)-3-ethoxycyclohexyl;4CG) (1S, 3S)-3-ethoxycyclohexyl; 4CH) (1R,3S)-3-ethoxy-2-fluorocyclobutyl; 4CI) (1S,3S)-3-ethoxy-2-fluorocyclobutyl; 4CJ) (1R,3R)-3-ethoxy-2-fluorocyclobutyl; 4CK) (1S,3R)-3-ethoxy-2-fluorocyclobutyl; or 4CL) tetrahydrofuran-3-yl.

A person of ordinary skill in the art will understand that any of 4A to4CL may be combined in Formula 1 with any of 1A to 1Q, any of 2A to 2Kand any of 3A to 3D, or 3E, to form any and all combinations betweensuch substituents.

In some embodiments, R is heteroaryl, leading to compounds havingformula 2

With respect to formula 2, Het-2 is a heteroaryl, and may comprise asingle ring or multiple rings, such as in a fused ring system. x is from1 to the number of possible substituents on the particular system inquestion, such as from 1 to 2, 3, 4, 5, or at least 6, and each R³independently is as previously defined for formula 1. Het-2 can beunsubstituted (if R³ is H for all occurrences on that particular moiety)or substituted. In particular embodiments of formula 2, Het-2 is nottetrazolyl or oxadiazolyl.

Het-2 may be a 5- or 6-membered heteroaryl. In some examples, Het-2 isfuran; thiophene; pyrazole; pyrrole; imidazole; oxazole; thiazole;isoxazole; isothiazole; triazole, such as 1,2,3-triazole,1,2,4-triazole, or 1,3,4-triazole; oxadiazole, such as 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,3,4-oxadiazole or 1,2,5-oxadiazole; thiadiazole,such as 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole or1,2,5-thiadiazole; tetrazole; pyrimidine; pyridine; triazine, such as1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine; pyrazine; orpyridazine. In particular examples, Het-2 is: pyridine, such aspyrid-2-yl, pyrid-3-yl or pyrid-4-yl; pyrimidine, such aspyramidin-2-yl; pyramidin-4-yl or pyramidin-5-yl; pyrazine, such aspyrazine-2-yl; or thiazole, such as thiazol-2-yl, thiazol-4-yl orthiazol-5-yl.

In some embodiments of formula 2, Het-1 is a substituted heteroaryl. Insome embodiments, Het-1 is substituted with at least a heterocyclemoiety, leading to compounds having formula 3

With reference to formula 3, Het-1, R, Het-2, R², R³, x and y are asdefined above for formulas 1 and 2. Het-3 is a heterocycle, and may beunsubstituted (if R³ is H for all occurrences on Het-3) or substituted.z is from 1 to the number of possible substituents on the particularsystem in question, such as from 1 to 2, 3, 4, 5, or at least 6.

In some embodiments of formula 3, Het-3 is a 5- or 6-memberedheterocycle, such as a 5- or 6-membered heteroaryl or heteroalicyclylmoiety. In some embodiments, Het-3 is furan; thiophene; pyrazole, suchas pyrazol-3-yl, or pyrazol-4-yl; pyrrole; imidazole; oxazole; thiazole;isoxazole; isothiazole; triazole, such as 1,2,3-triazole,1,2,4-triazole, or 1,3,4-triazole; oxadiazole, such as 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,3,4-oxadiazole or 1,2,5-oxadiazole; thiadiazole,such as 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole or1,2,5-thiadiazole; tetrazole; pyrimidine; pyridine; triazine, such as1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine; pyrazine; orpyridazine. In some embodiments, Het-3 is not pyridinyl. In certainembodiments, Het-3 is not pyridinyl, thiophenyl, furyl, pyrazinyl,quinolinyl, or pyrrolopyridinyl. In particular embodiments, Het-3 ispyrazole, and may be pyrazol-4-yl. Each of R³ independently may be H,aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, such asaralkyl, NO₂, CN, OH, haloalkyl, such as CF₃, alkyl phosphate oralkylphosphonate.

With respect to formula 3 and any of the Het-1 embodiments 1A to 1Q, anyof the R embodiments 2A to 2AB, any of the R¹ embodiments 3A to 3D, orthe combined R and R′ embodiment 3E, and any of the R² embodiments 4A to4CL, Het-3 may be, in any combination with 1A to 1Q, 2A to 2AB, 3A to3D, or 3E, and 4A to 4CL: 5A) a 5-membered heteroaryl; 5B) a 6-memberedheteroaryl; 5C) pyrazole; 5D) pyrrole; 5E) pyrazol-4-yl; 5F)pyrrol-3-yl; 5G) 5-nitropyrrol-3-yl; 5H) 1-methylpyrazol-4-yl; 51)1-(tert-butoxycarbonyl)pyrazol-4-yl; 5J) 3-methylpyrazol-4-yl; 5K)1-(((di-tert-butoxyphosphoryl)oxy)methyl)pyrazol-4-yl; 5L)1-(((tert-butoxy(hydroxy)phosphoryl)oxy)methyl)pyrazol-4-yl; 5M)1-((phosphonooxy)methyl)pyrazol-4-yl; 5N) 3-trifluoromethylpyrazol-4-yl;50) 1-((1-(isobutyryloxy)ethoxy)carbonyl)pyrazol-4-yl; 5P)1-((tert-butoxycarbonyl)-D-valyl)pyrazol-4-yl; 5Q)1-((1-methylcyclopropoxy)carbonyl)pyrazol-4-yl; 5R)1-(((1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl)oxy)carbonyl)pyrazol-4-yl;5S) 1-((phosphonooxy)methyl)pyrazol-4-yl sodium salt; 5T)1-ethylpyrazol-4-yl; 5U) 1-isopentylpyrazol-4-yl; 5V)1-((3-methyloxetan-3-yl)methyl)pyrazol-4-yl; 5W)1-(2-(2-methoxyethoxy)ethyl)pyrazol-4-yl; 5X) 3,5-dimethylpyrazol-4-yl;5Y) 1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)pyrazol-4-yl; 5Z)1-((diethoxyphosphoryl)methyl)pyrazol-4-yl; 5AA)1-(phosphonomethyl)pyrazol-4-yl; 5AB) 1-(phosphonomethyl)pyrazol-4-ylsodium salt; 5AC) 1-((phosphonooxy)methyl)pyrazol-4-yl potassium salt;5AD) 1-(4-methoxybenzyl)pyrazol-4-yl; 5AE) pyrazol-3-yl; 5AF)1-(cyclobutyl)pyrazol-4-yl; 5AG)5-fluoro-1-((2-(trimethyl-X⁴-sulfanyl)ethoxy)methyl)-pyrazol-4-yl; 5AH)5-fluoropyrazol-4-yl; 5AI) 1-((phosphonooxy)methyl)pyrazol-4-yl calciumsalt; 5AJ) 1-((phosphonooxy)methyl)pyrazol-4-yl ammonium salt; 5AK)1-((phosphonooxy)methyl)pyrazol-4-yl lysine salt; 5AL)1-((phosphonooxy)methyl)pyrazol-4-yl arginine salt; 5AM)1-((phosphonooxy)methyl)pyrazol-4-yl tris(hydroxymethyl)aminomethanesalt; 5AN) 1-((phosphonooxy)methyl)pyrazol-4-yl triethylamine salt; 5AO)1-(2,2,2-trifluoroethyl)pyrazol-4-yl; or 5AP)1-difluoromethylpyrazol-4-yl.

A person of ordinary skill in the art will understand that any of 5A to5AP may be combined with any of 1A to 1Q, any of 2A to 2AB and any of 3Ato 3D, or 3E, and any of 4A to 4CL, to form any and all combinationsbetween such substituents.

In some embodiments of formula 3, Het-2 is pyridine, leading tocompounds having formula 4

In certain embodiments of formula 4, the pyridine ring is 2-pyridyl,leading to compounds having formula 5

With reference to formula 4 and formula 5, R⁴-R⁷ are each independentlyH, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic,—O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl,carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl orsulfinyl. In some embodiments, R⁴-R⁷ are each independently H,aliphatic, halogen, haloalkyl, heteroaliphatic, alkoxy, heterocyclyl, or—O-heterocyclyl. In particular embodiments, R⁴-R⁷ may be independentlyH, halogen, haloalkyl, alkyl, heterocyclyl, alkoxy, or —O— heterocyclyl.In one embodiment of the compounds according to formulas 4 and 5, atleast one of R⁴-R⁷ is not H, for example, in one embodiment R⁴ is not H.

In certain embodiments, each of R⁴, R⁵, R⁶, and R⁷ independently isR^(a), R^(b), R^(a) substituted with R^(c), —OR^(a),—O—(CR^(a)R^(a))_(p)—R^(b) wherein p is 1, 2 or 3, and R^(a), R^(b) andR^(c) are as previously defined. In specific examples, R⁵ is H, F, CF₃,methoxy, morpholin-4-yl, 1-methylpiperidin-4-yl, —O—CH₂C(CH₃)₂OH, or—O-(oxetan-3-yl), and/or R⁴, R⁶ and R⁷ are H, F or CF₃.

In some embodiments of formula 4, Het-3 is a pyrazole, leading tocompounds having a general formula 6

Certain embodiments of formula 6 further satisfy formula 7

With reference to formula 6 and formula 7, R²-R⁷ and Het-1 are aspreviously defined for formula 5; R⁸, R⁹ and R¹⁰ are each independentlyH, aliphatic, heteroaliphatic, aryl, —O-aliphatic, such as alkoxy,araliphatic, such as aralkyl, heterocyclyl, sulfonyl, nitro, OH,haloalkyl, carboxyl ester, cyano, acyl, amino, alkyl phosphate oralkylphosphonate. R¹⁰ may be H, aliphatic, —O-aliphatic, such as alkoxy,heteroaliphatic, carboxyl ester, acyl, araliphatic, such as aralkyl,NO₂, CN, OH, haloalkyl, such as CF₃, alkyl phosphate oralkylphosphonate. In particular examples, R¹⁰ is H, alkyl, carboxylester, acyl, alkyl phosphate, alkyl phosphonate, heterocycloalkyl oraralkyl. In certain examples, R⁸ and R⁹ are each independently, H, alkylor haloalkyl, such as trifluoromethyl. In certain embodiments, Het-1 isfuran, thiazole or oxazole, and in particular embodiments, R⁸ and R⁹ areboth H, one of R⁸ and R⁹ is H and the other is lower alkyl, such asmethyl, or trifluoromethyl, or both of R⁸ and R⁹ are lower alkyl.

In some embodiments of formulas 6-7, R¹⁰ is R^(a), R^(b), R^(a)substituted with —OP(O)(R′)₂, R^(a) substituted with 1, 2 or 3 R^(b),R^(a) substituted with R^(c), R^(a) substituted with —P(O)(R^(f))₂,aralkyl, —(CR^(a)R^(a))_(n)—R^(a), —(CH₂)_(n)—R^(a) or—C(O)C(R^(a))₂NR^(a)R^(b), wherein n, R^(a), R^(b) and R^(c) are aspreviously defined, and R^(f) is independently for each occurrence—OR^(a), —O⁻M⁺ where each M⁺ independently is an alkali metal ion, suchas K⁺, Na⁺, Li⁺ or an ammonium ion, such as +NH₄ or ⁺N(R^(a))₄, or—O⁻[M²⁺]_(0.5) where M²⁺ is an alkaline metal earth ion, such as Mg²⁺,Ca²⁺ or Ba²⁺. In certain examples of the compounds of formulas 6-7, R¹⁰is —CH₂OP(O)(OH)₂, or a salt thereof.

In other embodiments of formula 5, Het-1 is furan, thiazole or oxazole,such as furan-2-yl, furan-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl or oxazol-5-yl. In certainembodiments, the compound has a general formula selected from

With reference to formulas 8, 9 and 10, R²-R⁷, Het-3 and z are aspreviously defined for formula 5; and R¹¹-R¹⁴ are each independently H,aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro,carboxyl ester, cyano or amino. In certain embodiments, the compound hasa formula selected from

With reference to formulas 11, 12 and 13, R²-R⁷, z and Het-3 are aspreviously defined for formula 5; R¹¹-R¹⁴ may be each independently H,C₁₋₆alkyl, CF₃, acyl, CN, or OH. In certain examples, R¹¹, R¹², R¹³ andR¹⁴ are each independently H or alkyl, and in particular examples, R¹¹,R¹², R¹³ and R¹⁴ are H.

In some embodiments of formulas 8-13, Het-3 is a pyrazole, such as apyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl. In particularembodiments, the compound has a formula selected from

where R²-R¹⁰ are as defined with respect to formula 7.

In certain embodiments of formula 1, R and R¹ together with the atoms towhich they are attached, form a heterocylyl ring. In certain embodimentof formula 1, compounds have a formula selected from

wherein Het-3 is heteroaryl.

In other embodiments of formula 1, R is aliphatic, such as alkyl,particularly CF₃; CN; or amide. In certain embodiments of formula 1,compound may have a formula selected from

wherein Het-3 is heteroaryl. With respect to formulas 20 and 30-32, eachof R¹⁵ and R¹⁶ independently is H; aliphatic, such as alkyl,particularly methyl; aryl; heteroaryl; or together with the nitrogen towhich they are attached, form a heterocyclyl ring, such as morpholine,piperidine, or piperazine.

In some embodiments of formulas 17-32, Het-3 is pyrazole, and in certainembodiments the

moiety is

where R⁸, R⁹ and R¹⁰ are as previously defined.

In certain embodiments of any of the above formulas, R⁴, R⁶, R⁷ are H,halogen, or haloalkyl; R⁵ is H, halogen, haloalkyl, alkoxy orN(R^(d)R^(d)) where each R^(d) independently is as previously defined;R¹¹, R¹², R¹³ and R¹⁴ are H; and R⁸ and R⁹ are both H, or one of R⁸ andR⁹ is H and the other is methyl or trifluoromethyl, or both of R⁸ and R⁹are methyl. In some embodiment, each of R⁴, R⁵, R^(6′) and R⁷independently is H, F or CF₃.

Some exemplary compounds according to formula 1 include:

In other embodiments, the compound according to formula 1 is selectedfrom

In other embodiments, the compound according to formula 1 is selectedfrom

Exemplary compounds according to formula 1 include:

-   I-1:    N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide    2,2,2-trifluoroacetate;-   I-2:    N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-3:    N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-4: tert-butyl    4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;-   I-5:    N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-6:    N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide    formic acid;-   I-7:    N-(1-(2-methoxyethyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-8:    N-(1-(2-methoxyethyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-H-pyrazol-4-yl)furan-2-carboxamide;-   I-9:    N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-10: di-tert-butyl    ((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)    phosphate;-   I-11: tert-butyl    ((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)    hydrogen phosphate;-   I-12:    (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   I-13:    N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-14: sodium    (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   I-15:    N-(1-(2-hydroxyethyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-16:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-17:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    hydrochloride salt;-   I-18:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-19: 1-(isobutyryloxy)ethyl    4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;-   I-20: tert-butyl    (S)-(1-(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate;-   I-21: 1-methylcyclopropyl    4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;-   I-22: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl    4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;-   I-23:    5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-24:    5-(5-nitro-1H-pyrrol-3-yl)-N-(1-(propoxymethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-25:    N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-26:    5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-27:    N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-28:    N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-29:    N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-30:    5-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-31:    N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-32:    N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-33:    N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-34:    N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-35:    (4-(5-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl    phosphate bis-sodium salt;-   I-36:    (4-(5-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   I-37:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-38:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-39:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-40:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-41:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-42:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-43:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-44:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-45:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-46:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-47:    5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-48:    5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-49:    5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-50:    N-(2-(2-methoxyethoxy)ethyl)-5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-51:    N-(2-(2-methoxyethoxy)ethyl)-5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-52:    5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-53:    5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-54:    (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   I-55: sodium    (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   I-56:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-57:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-58:    5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-59:    5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-60:    5-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-61:    5-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-62:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-63:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-64:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-65:    5-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-66:    5-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-67:    N-{1-Methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt;-   I-68:    5-(1-Methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide;-   I-69:    5-(1-Methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide,    formate salt;-   I-70:    tert-Butyl-3-[4-{5-(1H-pyrazole-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate,    formate salt;-   I-71:    N-{1-(3-Methoxycyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt, Cis isomer;-   I-72:    N-{1-(3-Methoxycyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    Cis isomer;-   I-73:    N-{1-(3-Benzyloxy)cyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    Trans isomer;-   I-74:    tert-Butyl-3-[4-{5-(1H-pyrazole-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate;-   I-75:    N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-76:    N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-77:    N-{1-Methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    free base;-   I-78:    N-{1-(Azetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    TFA salt;-   I-79:    N-{1-(Azetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-80:    Di-tert-butyl-[[4-{4-(5-((1-methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl}methyl]phosphate;-   I-81:    [4-{5-((1-Methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2yl}-1H-pyrazol-1-yl]methyl    dihydrogen phosphate;-   I-82: Sodium    [4-{5-((1-Methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl}-1H-pyrazol-1-yl]methyl    phosphate;-   I-83:    N-{1-(1-Acetylazetidin-3-yl)-3-(pyridine-2-yl}-1H-pyrazol-4-yl-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    free base;-   I-84:    3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-(tert-butyl)azetidine-1-carboxamide,    free base;-   I-85:    3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-isopropylazetidine-1-carboxamide,    free base;-   I-86:    3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-propylazetidine-1-carboxamide,    free base.-   I-87:    3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide,    formate salt;-   I-88:    3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide;-   I-89:    N-[1-{1-(Cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt;-   I-90:    N-[1-{1-(Cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-91:    N-[1-{1-Pivaloylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt;-   I-92:    N-[1-{1-Pivaloylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-93:    5-(1H-Pyrazol-4-yl)-N-{3-(pyridine-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt;-   I-94:    5-(1H-Pyrazol-4-yl)-N-{3-(pyridine-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-95:    N-[1-{1-Isobutyrylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt;-   I-96:    N-[1-{1-Isobutyrylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-97:    N-(1H-Pyrazol-4-yl)-N-{3-(pyridine-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide,    TFA salt;-   I-98:    N-(1H-Pyrazol-4-yl)-N-{3-(pyridine-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide;-   I-99:    N-[1-{1-Butyrylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt;-   I-100:    N-[1-{1-Butyrylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-101:    N-{1-(1-Methylazetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt;-   I-102:    N-{1-(1-Methylazetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-103:    N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,    formate salt;-   I-104:    N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-105:    N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-106:    N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-107:    N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-108:    N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-109:    N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-110:    N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-111:    N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-112:    N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-113:    5-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-114:    N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-115:    N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-116:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-117:    5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-118:    N-(1-(2-ethoxyethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-119:    N-(1-(2-ethoxyethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-120:    5-(1H-pyrazol-4-yl)-N-(1-(tetrahydrofuran-3-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-121:    5-(1H-pyrazol-4-yl)-N-(1-(tetrahydrofuran-3-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-122:    5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide    2,2,2-trifluoroacetate;-   I-123:    5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-124:    N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-125:    N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-126:    N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-127:    N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-128:    5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-129:    5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-130:    N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-131:    N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-132:    N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-133:    N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-134:    N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-135:    N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-136:    N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-137:    N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-138:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-139:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-140:    N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-141:    N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-142:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-143:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-144:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-145:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-146:    5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-147:    5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide;-   I-148:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-149:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-150:    N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-151:    N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-152:    N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-153:    N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;-   I-154:    N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide    formate;-   I-155:    N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;    or-   I-156:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide.

Exemplary embodiments of a compound according to formula 1 also include:

-   II-1:    N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-2: 1-(isobutyryloxy)ethyl    4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;-   II-3: tert-butyl    (R)-(3-methyl-1-(4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-1-oxobutan-2-yl)carbamate;-   II-4:    2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-5: 1-methylcyclopropyl    4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;-   II-6: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl    4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;-   II-7: diethyl    ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate;-   II-8: sodium    ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate;-   II-9:    ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonic    acid;-   II-10:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-11:    N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-12:    N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-13:    N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-14:    N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-15:    N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-16:    (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate bis-sodium salt;-   II-17:    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   II-18:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide,    formic acid salt;-   II-19:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide,    formic acid salt;-   II-20:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-21:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide,    formic acid salt;-   II-22:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-23:    2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide,    formic acid salt;-   II-24:    2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-25:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-26:    N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-27:    2-(3-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-28:    N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-29:    N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide,    formic acid salt;-   II-30:    N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-31:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-32:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-33:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-34:    N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-35:    (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   II-36: Sodium    (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   II-37:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-38: potassium    (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   II-39:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-40:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-41:    2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide,    formic acid salt;-   II-42:    2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-43:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-44:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-45:    2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-46:    2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-47:    N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-48:    N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-49:    N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide,    formic acid salt;-   II-50:    N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-51:    2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-52:    N-(1-(2-fluoroethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-53:    2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-54:    tert-Butyl-3-[4-{2-(1H-pyrazole-4-yl)thiazole-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate,    free base;-   II-55:    N-{1-(Azetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide,    TFA salt;-   II-56:    N-{1-(Azetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-57:    N-{1-(3-Methoxycyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide,    free base, Cis isomer;-   II-58:    N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-59:    N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-60:    N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-61:    N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-62:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-63:    N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    2,2,2-trifluoroacetate;-   II-64:    N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-65:    N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-66:    2-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-67:    (2-(1H-pyrazol-4-yl)thiazol-4-yl)(2-((1s,3s)-3-ethoxycyclobutyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone;-   II-68:    (2-(1H-pyrazol-4-yl)thiazol-4-yl)(2-((1s,3s)-3-ethoxycyclobutyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone    2,2,2-trifluoroacetate;-   II-69:    (2-(1H-pyrazol-4-yl)thiazol-4-yl)(1-(3-ethoxycyclobutyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone    2,2,2-trifluoroacetate;-   II-70:    N-(3-carbamoyl-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-71:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-72:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-73:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-74:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-75:    N-(3-(1,3,4-oxadiazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-76:    N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-77: potassium    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   II-78: calcium    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   II-79:    N-(1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-80: ammonium    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   II-81: 5-amino-5-carboxypentan-1-aminium    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   II-82: 1-(4-amino-4-carboxybutyl)guanidinium    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   II-83:    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   II-84: 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    hydrogen phosphate;-   II-85: triethylammonium    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    hydrogen phosphate;-   II-86:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-87:    N-(1-(3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-88:    N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-89:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-90:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-91:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-92:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-93:    2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-94:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-95:    N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-96:    N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-97:    N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-98:    2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-99:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-100:    2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-101:    N-(1-((1s,3s)-3-hydroxycyclobutyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-102:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-103:    2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-104:    2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-105:    N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-106:    N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-107:    2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-108:    2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-109:    N-(1-(2-ethoxyethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-110:    N-(1-(2-ethoxyethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-111:    2-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-112:    2-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-113:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-114:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-115:    2-(1H-pyrazol-4-yl)-N-(1-(tetrahydrofuran-3-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-116:    2-(1H-pyrazol-4-yl)-N-(1-(tetrahydrofuran-3-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-117:    N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-118:    N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-119:    N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-120:    N-(1-benzyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-121:    N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-122:    N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-123:    N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-124:    N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-125:    N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-126:    N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-127:    N-(1-((1s,3s)-3-(ethoxy-d5)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-128:    N-(1-(diethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-129:    N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-130:    N-(1-((1s,3s)-3-(2-fluoroethoxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-131:    N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-132:    N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-133:    N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-134:    N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-135:    N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-136:    N-(3-cyano-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-137:    N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-138:    N-(3-cyano-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-139:    N-(3-cyano-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-140:    N-(3-(3-fluoropyridin-2-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-141:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-142:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-143:    N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-144:    N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-145:    N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-146:    N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-147:    N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-148:    N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-149:    N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-150:    N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-151:    N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-152:    N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-153:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-154:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-155:    N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-156:    N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-157:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-158:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-159:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-160:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-161:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-162:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-163:    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   II-164: sodium    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate;-   II-165:    N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-166:    N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-167:    N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-168:    N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-169:    N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-170:    N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    formate;-   II-171:    N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-172:    N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-173:    (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   II-174:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-175:    N-(1-((1s,4s)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-176:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-177:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,4s)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-178:    N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   II-179:    N-(1-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;    or-   II-180:    N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide.

In other embodiments, the compound according to formula 1 is

-   III-1:    2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;-   III-2:    2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;-   III-3:    N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;-   III-4:    N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;-   III-5:    N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;-   III-6:    N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;-   III-7:    N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;    or-   III-8:    N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide.

B. Synthesis

Disclosed pyrazole compounds can be prepared as exemplified below, andas will be understood by a person of ordinary skill in the art inorganic synthesis. An exemplary synthesis may include the following1^(st) reaction step according to Scheme 1:

Acetyl compound 2 is reacted with dimethylformamide dimethylacetal 4 toform intermediate compound 6, at a temperature suitable to facilitate areaction. A suitable temperature is typically from 85° C. to 130° C.Intermediate compound 6 is then reacted with hydrazine hydrate 8 to formthe pyrazole compound 10. The reaction is performed in a suitablesolvent, for example, an alcohol such as ethanol, methanol orisopropanol, and is typically heated, such as to reflux.

A 2^(nd) reaction step in the exemplary synthesis is provided belowaccording to Scheme 2:

Compound 10 is nitrated using a suitable nitrating reagent or mixture ofreagents 12 to form compound 14. Suitable nitrating conditions includereacting compound 10 with nitric acid, such as fuming nitric acid,optionally in the presence of sulfuric acid. Typically, compound 10 andthe nitric acid are added slowly, one to the other. Cooling, such as byan ice bath, may be used to maintain the reaction temperature within asuitable range, such as from about 0° C. to less than 50° C., from 0° C.to 20° C., or from 0 OC to 10° C. After the addition is complete thereaction is allowed to proceed until the reaction is substantiallycomplete, and may be allowed to warm to room temperature to facilitatethe reaction. Optionally, additional nitrating reagent, or mixture ofnitrating reagents, may be added to facilitate the reaction proceedingto completion. The reaction is then quenched, such as by addition towater and/or ice, and the product is separated or extracted from theaqueous and purified if required. Purification techniques suitable forpurifying a product from any reaction disclosed herein include, but arenot limited to, crystallization, distillation and/or chromatography.

With continued reference to Scheme 2, compound 14 is then reacted withcompound 16 to form compound 18. Compound 16 comprises a desired R¹moiety and a suitable leaving group, LG. Suitable leaving groups includeany group that will act as a leaving group to facilitate the addition ofthe R¹ moiety to compound 14. Suitable leaving groups include, but arenot limited to, halogens, typically bromo, chloro or iodo, and tosylateor mesylate groups. Compound 14 is reacted with compound 16 in asuitable solvent and typically in the presence of a base. Suitablesolvents include any solvent that facilitates the reaction, such asaprotic solvents. Suitable solvents include, but are not limited to,DMF, THF, DMSO, acetonitrile, chlorinated solvents such asdichloromethane and chloroform, DMA, dioxane, N-methyl pyrrolidone, orcombinations thereof. Suitable bases include any base that willfacilitate the reactions, such as a hydride, typically sodium hydride,or a carbonate, such as potassium carbonate, sodium carbonate, or cesiumcarbonate. The reaction may be heated, such as to 50° C., 100° C. orhigher, as required, or the reaction may proceed at room temperature.Compound 18 is then isolated from the reaction mixture and purified ifrequired.

Compound 18 is then reacted with a reducing agent 20 suitable to reducethe nitro moiety to an amine. Suitable reducing agents include, but arenot limited to: hydrogen gas in the presence of a catalyst, such as apalladium catalyst; a borohydride, such as sodium borohydride,optionally in the presence of a catalyst, such as a nickel catalyst;zinc metal in acetic acid; or iron powder in water or water and acid. Incertain embodiments, hydrogen gas is used, in the presence of apalladium on carbon catalyst, and in a suitable solvent, such as ethylacetate or methanol. In some embodiments, a combination of reducingagents and/or techniques are used. For example, reduction may beinitially performed using a first method comprising a first reducingagent and/or technique, but result in a mixture of products. The firstmethod may be repeated, and/or a second method may be performed,comprising a second reducing agent and/or technique. Once the reactionis complete, as indicated by an analytical technique such as LC-MS, TLCor HPLC, the product compound 22 is isolated and purified if necessary.

A 3^(rd) step of the exemplary reaction sequence is provided belowaccording to Scheme 3:

Compound 22 is reacted with a carboxylic acid 24 to form compound 26.The carboxylic acid 24 is activated by any suitable method and thenreacted with the amine on compound 22. Suitable activation methodsinclude, but are not limited to: forming the acid chloride by treatmentwith thionyl chloride; by treatment with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) and a base such asdiisopropylethylamine (DIPEA); by treatment with carbonyldiimidazole(CDI); or by treatment with a carbodiimide, such asdicyclohexylcarbodiimide (DCC) or1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

Compound 26 is then coupled with compound 28 to form compound 30 usingany coupling reaction suitable to form a bond between two rings. In theexample above, a boronic acid coupling is shown, where the leaving groupLG on compound 26 is typically bromo or iodo. Other suitable couplingfunctional groups include trialkyl tin or boronic esters. The couplingreaction typically proceeds in the presence of a suitable catalyst. Fora boronic acid coupling, the catalyst typically is a palladium catalyst,such as PdCl₂(dppf)₂, Pd[P(Ph)₃]₂Cl₂, palladium acetate and triphenylphosphine, or tetrakis(triphenylphosphine)palladium(0). The reaction isperformed in the presence of a base, such as sodium, potassium or cesiumcarbonate, and is performed in a suitable solvent or solvent mixture,such as dioxane, dioxane/water or DME/ethanol/water. The reaction may beheated at a suitable temperature, such as from 50° C. to 125° C.,typically about 100° C., and/or agitated for a suitable period of time,such as from 1 hour to 3 days, from 6 hours to 24 hours, or from 12hours to 18 hours, to facilitate the reaction proceeding to completion.Compound 30 is then isolated from the reaction mixture and purified by asuitable technique.

An alternative exemplary synthesis may include the following 1^(st)reaction step according to Scheme 4:

Compound 32 is nitrated using a suitable nitrating reagent or mixture ofreagents 34 to form compound 36. Suitable nitrating conditions includereacting compound 32 with nitric acid, such as fuming nitric acid,optionally in the presence of sulfuric acid. Typically, compound 32 andthe nitric acid are added slowly, one to the other. Cooling, such as byan ice bath, may be used to maintain the reaction temperature within asuitable range, such as from about 0° C. to less than 50° C., from 0° C.to 20° C., or from 0 OC to 10° C. After the addition is complete thereaction is allowed to proceed until the reaction is substantiallycomplete, and may be allowed to warm to room temperature to facilitatethe reaction. Optionally, additional nitrating reagent, or mixture ofnitrating reagents, may be added to facilitate the reaction proceedingto completion. The reaction is then quenched, such as by addition towater and/or ice, and the product is separated or extracted from theaqueous and purified if required. Purification techniques suitable forpurifying a product from any reaction disclosed herein include, but arenot limited to, crystallization, distillation and/or chromatography.

With continued reference to Scheme 4, compound 36 is then reacted withcompound 38 to form compound 40. Compound 38 comprises a desired ring,such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, and a suitableleaving group, LG. Suitable leaving groups include any group that willact as a leaving group to facilitate the addition of the ring tocompound 36. Suitable leaving groups include, but are not limited to,halogens, typically bromo, chloro or iodo, and tosylate or mesylategroups. Compound 36 is reacted with compound 38 in a suitable solventand typically in the presence of a base. Suitable solvents include anysolvent that facilitates the reaction, such as aprotic solvents.Suitable solvents include, but are not limited to, DMF, THF, DMSO,acetonitrile, chlorinated solvents such as dichloromethane andchloroform, DMA, dioxane, N-methyl pyrrolidone, or combinations thereof.Suitable bases include any base that will facilitate the reactions, suchas a hydride, typically sodium hydride, or a carbonate, such aspotassium carbonate, sodium carbonate, or cesium carbonate. The reactionmay be heated, such as to 50° C., 100° C. or higher, as required, or thereaction may proceed at room temperature. Compound 40 is then isolatedfrom the reaction mixture and purified if required.

Compound 40 is then reacted with a reducing agent 42 suitable to reducethe carbonyl moiety to a hydroxyl. Suitable reducing agents include, butare not limited to, sodium borohydride, di-isobutyl aluminum hydride, orlithium aluminum hydride. The reaction is performed in a solventsuitable to facilitate the reaction, such as an alcohol, particularlymethanol or ethanol; THF; or diethyl ether. The reaction may be heated,such as to 50° C., 100° C. or higher, as required, cooled, such as tobelow 20° C., below 10° C., below 0° C. or lower, or the reaction mayproceed at room temperature. Once the reaction is complete, as indicatedby an analytical technique such as LC-MS, TLC or HPLC, the productcompound 44 is isolated and purified if necessary, by a suitabletechnique, such as column chromatography.

Optionally, compound 44 may be reacted with compound 46 to form compound48. Compound 46 comprises a desired Rx moiety and a suitable leavinggroup, LG. Suitable leaving groups include any group that will act as aleaving group to facilitate the addition of the RX moiety to compound44. Suitable leaving groups include, but are not limited to, halogens,typically bromo, chloro or iodo, and tosylate or mesylate groups.Compound 44 is reacted with compound 46 in a suitable solvent andtypically in the presence of a base or other reagent or reagents thatfacilitate the reaction. Suitable solvents include any solvent thatfacilitates the reaction, such as aprotic solvents. Suitable solventsinclude, but are not limited to, DMF, THF, DMSO, acetonitrile,chlorinated solvents such as dichloromethane and chloroform, DMA,dioxane, N-methyl pyrrolidone, or combinations thereof. Suitable basesor reagents that facilitate the reaction include, but are not limitedto, silver triflate, 2,6-di-t-butylpyridine, sodium hydride, orcombinations thereof. Typically, compound 46 is slowly combined with thereaction. Cooling, such as by an ice bath, may be used to maintain thereaction temperature within a suitable range, such as from about 0° C.to less than 50° C., from 0° C. to 20° C., or from 0° C. to 10° C. Afterthe addition is complete the reaction is allowed to proceed until thereaction is substantially complete, and may be allowed to warm to roomtemperature, or the reaction may be heated, such as to 50° C., 100° C.or higher, to facilitate the reaction. Once the reaction is complete, asindicated by an analytical technique such as LC-MS, TLC or HPLC, theproduct compound 48 is isolated and purified if necessary, by a suitabletechnique, such as column chromatography.

Alternatively, compound 40 may be prepared by an exemplary syntheticroute according to Scheme 5:

With respect to Scheme 5, compound 36 is reacted with compound 50 toform compound 52. Compound 50 comprises a desired ring, such as acyclobutyl, cyclopentyl, or cyclohexyl ring, a suitable leaving group,LG, and a protected carbonyl moiety, such as an acetal or a ketal. Inthe example above a cyclic ketal moiety is shown. Suitable leavinggroups include any group that will act as a leaving group to facilitatethe addition of the ring to compound 36, and include, but are notlimited to, halogens, typically bromo, chloro or iodo, and tosylate ormesylate groups. Compound 36 is reacted with compound 50 in a suitablesolvent and typically in the presence of a base. Suitable solventsinclude any solvent that facilitates the reaction, such as aproticsolvents. Suitable solvents include, but are not limited to, DMF, THF,DMSO, acetonitrile, chlorinated solvents such as dichloromethane andchloroform, DMA, dioxane, N-methyl pyrrolidone, or combinations thereof.Suitable bases include any base that will facilitate the reactions, suchas a hydride, typically sodium hydride, or a carbonate, such aspotassium carbonate, sodium carbonate, or cesium carbonate. The reactionmay be heated, such as to 50° C., 100° C. or higher, as required, or thereaction may proceed at room temperature. Compound 52 is then isolatedfrom the reaction mixture and purified if required by a suitabletechnique, such as column chromatography.

Compound 52 is then reacted with a suitable reagent 54 to form compound40. Reagent 54 may be any reagent suitable to remove the protectinggroup and/or form the carbonyl moiety. In the exemplary synthesis shownin Scheme 5, the protecting group is a cyclic ketal, and suitablereagents 54 include, but are not limited to, pyridinium tosylate (PPTS),para-toluene sulfonic acid, hydrochloric acid, or acetic acid. Thereaction is performed in a solvent or mixture of solvents suitable tofacilitate the reaction, such as acetone, THF, acetic acid, water, or acombination thereof. The reaction may be heated, such as to 50° C., 100°C. or higher, or at reflux, as required, or the reaction may proceed atroom temperature. Compound 40 is then isolated from the reaction mixtureand purified if required by a suitable technique, such as columnchromatography.

A 2^(nd) step of the exemplary reaction sequence is provided belowaccording to Scheme 6:

Compound 48 is then reacted with a reducing agent 56 suitable to reducethe nitro moiety to an amine. In certain embodiments where the desiredproduct compound comprises a hydroxyl moiety, compound 44 may be used inplace of compound 48. Suitable reducing agents include, but are notlimited to: hydrogen gas in the presence of a catalyst, such as apalladium catalyst; a borohydride, such as sodium borohydride,optionally in the presence of a catalyst, such as a nickel catalyst;zinc metal in acetic acid; or iron powder in water or water and acid. Incertain embodiments, hydrogen gas is used, in the presence of apalladium on carbon catalyst, and in a suitable solvent, such as ethylacetate or methanol. In some embodiments, a combination of reducingagents and/or techniques are used. For example, reduction may beinitially performed using a first method comprising a first reducingagent and/or technique, but result in a mixture of products. The firstmethod may be repeated, and/or a second method may be performed,comprising a second reducing agent and/or technique. Once the reactionis complete, as indicated by an analytical technique such as LC-MS, TLCor HPLC, the product compound 58 is isolated and purified if necessary.

Compound 58 is reacted with a carboxylic acid 60 to form compound 62.The carboxylic acid 60 is activated by any suitable method and thenreacted with the amine on compound 58. Suitable activation methodsinclude, but are not limited to: forming the acid chloride by treatmentwith thionyl chloride; by treatment with1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) and a base such asdiisopropylethylamine (DIPEA); by treatment with carbonyldiimidazole(CDI); or by treatment with a carbodiimide, such asdicyclohexylcarbodiimide (DCC) or1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

Compound 62 is then coupled with compound 64 to form compound 66 usingany coupling reaction suitable to form a bond between two rings. In theexample above, a boronic ester coupling is shown, where the leavinggroup LG on compound 62 is typically bromo or iodo. Other suitablecoupling functional groups include trialkyl tin or boronic acids. Thecoupling reaction typically proceeds in the presence of a suitablecatalyst. For a boronic ester or boronic acid coupling, the catalysttypically is a palladium catalyst, such as PdCl₂(dppf)₂, Pd[P(Ph)₃]₂Cl₂,palladium acetate and triphenyl phosphine, ortetrakis(triphenylphosphine)palladium(0). The reaction is performed inthe presence of a base, such as sodium, potassium or cesium carbonate,and is performed in a suitable solvent or solvent mixture, such asdioxane, dioxane/water or DME/ethanol/water. The reaction may be heatedat a suitable temperature, such as from 50° C. to 125° C., typicallyabout 100° C., and/or agitated for a suitable period of time, such asfrom 1 hour to 3 days, from 6 hours to 24 hours, or from 12 hours to 18hours, to facilitate the reaction proceeding to completion. Compound 66is then isolated from the reaction mixture and purified by a suitabletechnique.

Certain embodiments may comprise a phosphate moiety. Scheme 7 providesan exemplary synthesis of certain such embodiments:

Compound 68 is reacted with compound 70 to form compound 72. Compound 70comprises desired R^(y) moieties and a suitable leaving group, LG.Typical R^(y) moieties include, but are not limited to aliphatic, suchas alkyl, typically methyl, ethyl, propyl, isopropyl or t-butyl; aryl;heteroaliphatic; or heterocyclic. The two R^(y) moieties may be the sameor different. Suitable leaving groups include, but are not limited to,halogens, typically bromo, chloro or iodo, and tosylate or mesylategroups. Compound 68 is reacted with compound 70 in a suitable solventand typically in the presence of a base. Suitable solvents include anysolvent that facilitates the reaction, such as aprotic solvents.Suitable solvents include, but are not limited to, DMF, THF, DMSO,acetonitrile, chlorinated solvents such as dichloromethane andchloroform, DMA, dioxane, N-methyl pyrrolidone, or combinations thereof.Suitable bases include any base that will facilitate the reactions, suchas a hydride, typically sodium hydride, or a carbonate, such aspotassium carbonate, sodium carbonate, or cesium carbonate. The reactionmay be heated, such as to 50° C., 100° C. or higher, as required, or thereaction may proceed at room temperature. Compound 72 is then isolatedfrom the reaction mixture and purified if required.

Compound 72 is then reacted with compound 74 to form compound 76.Compound 74 may be any compound suitable to form the acid moieties incompound 76. Compound 74 may be an acidic reagent, such astrifluoroacetic acid, hydrochloride acid, or hydrobromic acid, or it maybe a basic reagent, such as sodium hydroxide, lithium hydroxide orpotassium hydroxide. Suitable solvents include, but are not limited to,chlorinated solvents such as dichloromethane and chloroform, alcoholssuch as methanol and ethanol, water, or combinations thereof. Thereaction may be heated, such as to 50° C., 100° C. or higher, asrequired, cooled, such as to below 20° C., below 10° C., below 0° C. orlower, or the reaction may proceed at room temperature. Once thereaction is complete, as indicated by an analytical technique such asLC-MS, TLC or HPLC, the product compound 76 is isolated and purified ifnecessary, by a suitable technique, such as by agitating, such as bystirring or sonication, in a suitable solvent or solvent system.Suitable solvents or solvent systems include, but are not limited to,acetone/water, acetone, diethyl ether, or alcohol/water.

Compound 76 is then reacted with compound 78 to form the salt compound80. Compound 78 can be any compound that will provide a suitablecounterion CA for the salt compound 80, such as calcium hydroxide,sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia,trimethylamine, tris(hydroxymethyl)aminomethane, or an amino acid suchas lysine or arginine. A person of ordinary skill in the art willappreciate that if counter ion CA has a single positive charge, as inNa⁺, K⁺, Li⁺, or NH₄, then compound 80 will comprise two CA ions,whereas if counter ion CA has two positive charges, as in CA²⁺ compound80 will comprise one CA ion.

C. Combinations of Therapeutic Agents

The pyrazole compounds of the present invention may be used alone, incombination with one another, or as an adjunct to, or in combinationwith, other established therapies. In another aspect, the compounds ofthe present invention may be used in combination with other therapeuticagents useful for the disorder or condition being treated. Thesecompounds may be administered simultaneously, sequentially in any order,by the same route of administration, or by a different route.

In some embodiments, the second therapeutic agent is an analgesic, anantibiotic, an anticoagulant, an antibody, an anti-inflammatory agent,an immunosuppressant, a guanylate cyclase-C agonist, an intestinalsecretagogue, an antiviral, anticancer, antifungal, or a combinationthereof. The anti-inflammatory agent may be a steroid or a nonsteroidalanti-inflammatory agent. In certain embodiments, the nonsteroidalanti-inflammatory agent is selected from aminosalicylates,cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen,flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin,meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen,oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combinationthereof. In some embodiments, the immunosuppressant is mercaptopurine, acorticosteroid, an alkylating agent, a calcineurin inhibitor, an inosinemonophosphate dehydrogenase inhibitor, antilymphocyte globulin,antithymocyte globulin, an anti-T-cell antibody, or a combinationthereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds may be used with otheranti-cancer or cytotoxic agents. Various classes of anti-cancer andanti-neoplastic compounds include, but are not limited to, alkylatingagents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes,antibiotics, enzymes, cytokines, platinum coordination complexes,proteasome inhibitors, substituted ureas, kinase inhibitors, hormonesand hormone antagonists, and hypomethylating agents, for example DNMTinhibitors, suchas azacitidine and decitabine. Exemplary alkylatingagents include, without limitation, mechlorothamine, cyclophosphamide,ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines,alkyl sulfonates (e.g., busulfan), and carmustine. Exemplaryantimetabolites include, by way of example and not limitation, folicacid analog methotrexate; pyrmidine analog fluorouracil, cytosinearbinoside; purine analogs mercaptopurine, thioguanine, andazathioprine. Exemplary vinca alkyloids include, by way of example andnot limitation, vinblastine, vincristine, paclitaxel, and colchicine.Exemplary antibiotics include, by way of example and not limitation,actinomycin D, daunorubicin, and bleomycin. An exemplary enzymeeffective as an anti-neoplastic agent includes L-asparaginase. Exemplarycoordination compounds include, by way of example and not limitation,cisplatin and carboplatin. Exemplary hormones and hormone relatedcompounds include, by way of example and not limitation,adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitorsamino glutethimide, formestane, and anastrozole; progestin compoundshydroxyprogesterone caproate, medroxyprogesterone; and anti-estrogencompound tamoxifen.

These and other useful anti-cancer compounds are described in MerckIndex, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001)and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12thEdition, Brunton L. L. ed., Chapters 60-63, McGraw Hill, (2011), both ofwhich are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with thepresently disclosed inhbitors is ipilimumab, marketed as YERVOY® byBristol-Myers Squibb.

Other chemotherapeutic agents for combination include immunooncologyagents, such as checkpoint pathway inhibitors, for example, PD-1inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors,such as pembrolizumab, MEDI-4736 and MPDL3280A/RG7446. Additionalcheckpoint inhibitors for combination with the compounds disclosedherein include, Anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

Further chemotherapeutic agents for combination with the presentlydisclosed inhibitors include Anti-SLAMF7 agents, such as the humanizedmonoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such asthe anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137agents, such as the fully human monoclonal antibody urelumab(BMS-663513).

Additional anti-proliferative compounds useful in combination with thecompounds of the present invention include, by way of example and notlimitation, antibodies directed against growth factor receptors (e.g.,anti-Her2); and cytokines such as interferon-α and interferon-γ,interleukin-2, and GM-CSF.

Additional chemotherapeutic agents useful in combination with thepresent pyrazole compounds include proteasome inhibitors, such asbortezomib, carfilzomib, marizomib and the like.

Examples of kinase inhibitors that are useful in combination with thepresently disclosed compounds, particularly in treating malignanciesinclude, Btk inhibitors, such as ibrutinib, CDK inhibitors, such aspalbociclib, EGFR inhibitors, such as afatinib, erlotinib, gefitinib,lapatinib, osimertinib and vandetinib, Mek inhibitors, such astrametinib, Raf inhibitors, such as dabrafenib, sorafenib andvemurafenib, VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib,pazopanib, BCR-Abl inhibitors, such as bosutinib, dasatinib, imatiniband nilotinib, Syk inhibitors, such as fostamatinib, and JAK inhibitors,such as ruxolitinib, In other embodiments, the second therapeutic agentmay be selected from any of the following:

analgesics-morphine, fentanyl, hydromorphone, oxycodone, codeine,acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine,flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

antibiotics-aminoglycosides (e.g., amikacin, gentamicin, kanamycin,neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g.,ertapenem, doripenem, imipenem, cilastatin, and meropenem),cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin,cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, andcefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, andtelavancin), lincosamides (e.g., clindamycin and incomysin),lipopeptides) e.g., daptomycin), macrolides (azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, and spectinomycin), monobactams (e.g.,aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin),penicilllins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,temocillin, and ticarcillin), penicillin combinations (e.g.,amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,and ticarcillin/clavulanate), polypeptides (e.g., bacitracin, colistin,and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin,gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, andtemafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole,sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole,trimethoprim, and trimethoprim-sulfamethoxaxzole), tetracyclines (e.g.,demeclocycline, doxycycline, minocycline, oxytetracycline, andtetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone,capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, andstreptomycin), and others, such as arsphenamine, chloramphenicol,fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin,platensimycin, quinuprisin/dalfopristin, rifaximin, thiamphenicol,tigecycline, and timidazole;

antibodies-anti-TNF-α antibodies, e.g., infliximab (Remicade™),adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g.,rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1antibodies, e.g., anakinra; anti PD-1 and/or anti-PD-L1 antibodies, e.g.nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224,MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab,clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab,sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants-warfarin (Coumadin™), acenocoumarol, phenprocoumon,atromentin, phenindione, heparin, fondaparinux, idraparinux,rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam,dabigatran, ximelagatran, batroxobin, hementin;

anti-inflammatory agents-steroids, e.g., budesonide, nonsteroidalanti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine,mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors(COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac,famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen,indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone,naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants-mercaptopurine, corticosteroids such asdexamethasone, hydrocortisone, prednisone, methylprednisolone andprednisolone, alkylating agents such as cyclophosphamide, calcineurininhibitors such as cyclosporine, sirolimus and tacrolimus, inhibitors ofinosine monophosphate dehydrogenase (IMPDH) such as mycophenolate,mycophenolate mofetil and azathioprine, and agents designed to suppresscellular immunity while leaving the recipient's humoral immunologicresponse intact, including various antibodies (for example,antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonalanti-T-cell antibodies (OKT3)) and irradiation. Azathioprine iscurrently available from Salix Pharmaceuticals, Inc. under the brandname Azasan; mercaptopurine is currently available from GatePharmaceuticals, Inc. under the brand name Purinethol; prednisone andprednisolone are currently available from Roxane Laboratories, Inc.;Methyl prednisolone is currently available from Pfizer; sirolimus(rapamycin) is currently available from Wyeth-Ayerst under the brandname Rapamune; tacrolimus is currently available from Fujisawa under thebrand name Prograf; cyclosporine is current available from Novartisunder the brand name Sandimmune and Abbott under the brand name Gengraf;IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid arecurrently available from Roche under the brand name Cellcept andNovartis under the brand name Myfortic; azathioprine is currentlyavailable from Glaxo Smith Kline under the brand name Imuran; andantibodies are currently available from Ortho Biotech under the brandname Orthoclone, Novartis under the brand name Simulect (basiliximab)and Roche under the brand name Zenapax (daclizumab); and

Guanylate cyclase-C receptor agonists or intestinal secretagogues—forexample linaclotide, sold under the name Linzess.

These various agents can be used in accordance with their standard orcommon dosages, as specified in the prescribing information accompanyingcommercially available forms of the drugs (see also, the prescribinginformation in the 2006 Edition of The Physician's Desk Reference), thedisclosures of which are incorporated herein by reference.

D. Compositions Comprising Pyrazole Compounds

The disclosed pyrazole compounds may be used alone, in any combination,and in combination with, or adjunctive to, at least one secondtherapeutic agent, and further the pyrazole compounds, and the at leastone second therapeutic, may be used in combination with any suitableadditive useful for forming compositions for administration to asubject. Additives can be included in pharmaceutical compositions for avariety of purposes, such as to dilute a composition for delivery to asubject, to facilitate processing of the formulation, to provideadvantageous material properties to the formulation, to facilitatedispersion from a delivery device, to stabilize the formulation (e.g.,antioxidants or buffers), to provide a pleasant or palatable taste orconsistency to the formulation, or the like. Typical additives include,by way of example and without limitation: pharmaceutically acceptableexcipients; pharmaceutically acceptable carriers; and/or adjuvants, suchas mono-, di-, and polysaccharides, sugar alcohols and other polyols,such as, lactose, glucose, raffinose, melezitose, lactitol, maltitol,trehalose, sucrose, mannitol, starch, or combinations thereof;surfactants, such as sorbitols, diphosphatidyl choline, and lecithin;bulking agents; buffers, such as phosphate and citrate buffers;antiadherents, such as magnesium stearate; binders, such as saccharides(including disaccharides, such as sucrose and lactose,), polysaccharides(such as starches, cellulose, microcrystalline cellulose, celluloseethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers(such as polyvinylpyrrolidone, polyalkylene gylcols); coatings (such ascellulose ethers, including hydroxypropylmethyl cellulose, shellac, cornprotein zein, and gelatin); release aids (such as enteric coatings);disintegrants (such as crospovidone, crosslinked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dibasiccalcium phosphate, vegetable fats and oils, lactose, sucrose, glucose,mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavorsand sweeteners (such as mint, cherry, anise, peach, apricot or licorice,raspberry, and vanilla; lubricants (such as minerals, exemplified bytalc or silica, fats, exemplified by vegetable stearin, magnesiumstearate or stearic acid); preservatives (such as antioxidantsexemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate, andselenium, amino acids, exemplified by cysteine and methionine, citricacid and sodium citrate, parabens, exemplified by methyl paraben andpropyl paraben); colorants; compression aids; emulsifying agents;encapsulation agents; gums; granulation agents; and combinationsthereof.

III. Methods of Use

A. Diseases/Disorders

The disclosed pyrazole compounds, as well as combinations and/orcompositions thereof, may be used to ameliorate, treat or prevent avariety of diseases and/or disorders. In particular embodiments, thepyrazole compound, combinations of pyrazole compounds, or compositionsthereof, may be used to treat or prevent auto-immune diseases,inflammatory disorders, cardiovascular diseases, nerve disorders,neurodegenerative disorders, allergic disorders, asthma, pancreatitis,multi-organ failure, kidney diseases, platelet aggregation, cancer,transplantation, sperm motility, erythrocyte deficiency, graftrejection, lung injuries, respiratory diseases, ischemic conditions, andbacterial and viral infections.

In some embodiments, the pyrazole compound, combinations of pyrazolecompounds, or compositions thereof, may be used to treat or preventallergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupuserythematosus, rheumatoid arthritis, type I diabetes mellitus,inflammatory bowel disease, biliary cirrhosis, uveitis, multiplesclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid,sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis,ichthyosis, Graves ophthalmopathy or asthma.

The pyrazole compound, combinations of pyrazole compounds, orcompositions thereof, may also be useful for ameliorating, treating orpreventing immune regulatory disorders related to bone marrow or organtransplant rejection or graft-versus-host disease. Examples ofinflammatory and immune regulatory disorders that can be treated withthe present compounds include, but are not limited to, transplantationof organs or tissue, graft-versus-host diseases brought about bytransplantation, autoimmune syndromes including rheumatoid arthritis,systemic lupus erythematosus, Hashimoto's thyroiditis, multiplesclerosis, systemic sclerosis, myasthenia gravis, type I diabetes,uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, postinfectious autoimmune diseases includingrheumatic fever and postinfectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, celiac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjögren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic liver disease, including alcoholic cirrhosis, non-alcoholicsteatohepatitis (NASH), hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, cancer, senile dementia, Parkinson's disease, trauma,or chronic bacterial infection.

In certain embodiments, the present compounds are useful for treatingnerve pain, including neuropathic pain and inflammation induced pain.

In certain embodiments, the pyrazole compound, combinations of pyrazolecompounds, or compositions thereof, are useful for treating and/orpreventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis,systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis,osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, inparticular pustular psoriasis, type I diabetes, type II diabetes,inflammatory bowel disease (Cronh's disease and ulcerative colitis),hyperimmunoglobulinemia d and periodic fever syndrome,cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemicjuvenile idiopathic arthritis, adult's onset Still's disease, gout, goutflares, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke,atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptorantagonist), Alzheimer's disease, Parkinson's disease.

Proliferative diseases that may be treated by the pyrazole compound,combinations of pyrazole compounds, or compositions thereof, includebenign or malignant tumors, solid tumor, carcinoma of the brain, kidney,liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries,colon, rectum, prostate, pancreas, lung, vagina, cervix, testis,genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma,glioblastomas, neuroblastomas, multiple myeloma, gastrointestinalcancer, especially colon carcinoma or colorectal adenoma, a tumor of theneck and head, an epidermal hyperproliferation, psoriasis, prostatehyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma,adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cellcarcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins andNon-Hodgkins, a mammary carcinoma, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,IL-1 driven disorders, a MyD88 driven disorder (such as ABC diffuselarge B-cell lymphoma (DLBCL), Waldenstrdm's macroglobulinemia,Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chroniclymphocytic leukemia), smoldering or indolent multiple myeloma, orhematological malignancies (including leukemia, acute myeloid leukemia(AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS),myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrdm'smacroglobulinemia (WM), splenic marginal zone lymphoma, multiplemyeloma, plasmacytoma, intravascular large B-cell lymphoma). Inparticular, the presently disclosed compounds are useful in treatingdrug resistant malignancies, such as those resistant to JAK inhibitorsibrutinib resistant malignancies, including ibrutinib resistanthematological malignancies, such as ibrutinib resistant CLL andibrutinib resistant Waldenstrdm's macroglobulinemia.

Examples of allergic disorders that may be treated using the pyrazolecompound, combinations of pyrazole compounds, or compositions thereof,include, but are not limited to, asthma (e.g. atopic asthma, allergicasthma, atopic bronchial IgE-mediated asthma, non-atopic asthma,bronchial asthma, non-allergic asthma, essential asthma, true asthma,intrinsic asthma caused by pathophysiologic disturbances, essentialasthma of unknown or unapparent cause, emphysematous asthma,exercise-induced asthma, emotion-induced asthma, extrinsic asthma causedby environmental factors, cold air induced asthma, occupational asthma,infective asthma caused by or associated with bacterial, fungal,protozoal, or viral infection, incipient asthma, wheezy infant syndrome,bronchiolitis, cough variant asthma or drug-induced asthma), allergicbronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennialallergic rhinitis, perennial rhinitis, vasomotor rhinitis, post-nasaldrip, purulent or non-purulent sinusitis, acute or chronic sinusitis,and ethmoid, frontal, maxillary, or sphenoid sinusitis.

As another example, rheumatoid arthritis (RA) typically results inswelling, pain, loss of motion and tenderness of target jointsthroughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdendritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The pyrazole compound, combinations of pyrazolecompounds, or compositions thereof, may be used to treat, ameliorate orprevent any one, several or all of these symptoms of RA. Thus, in thecontext of RA, the compounds are considered to provide therapeuticbenefit when a reduction or amelioration of any of the symptoms commonlyassociated with RA is achieved, regardless of whether the treatmentresults in a concomitant treatment of the underlying RA and/or areduction in the amount of circulating rheumatoid factor (“RF”).

The American College of Rheumatology (ACR) has developed criteria fordefining improvement and clinical remission in RA. Once such parameter,the ACR20 (ACR criteria for 20% clinical improvement), requires a 20%improvement in the tender and swollen joint count, as well as a 20%improvement in 3 of the following 5 parameters: patient's globalassessment, physician's global assessment, patient's assessment of pain,degree of disability, and level of acute phase reactant. These criteriahave been expanded for 50% and 70% improvement in ACR50 and ACR70,respectively. Other criteria include Paulu's criteria and radiographicprogression (e.g. Sharp score).

In some embodiments, therapeutic benefit in patients suffering from RAis achieved when the patient exhibits an ACR20. In specific embodiments,ACR improvements of ACRC50 or even ACR70 may be achieved.

B. Formulations and Administration

Pharmaceutical compositions comprising the active compounds of theinvention (or prodrugs thereof) may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions may be formulated in conventional manner using one or morephysiologically acceptable excipients, diluents, carriers, adjuvants orauxiliaries to provide preparations which can be used pharmaceutically.

The active compound or prodrug may be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide orpharmaceutically acceptable salt. Typically, such salts are more solublein aqueous solutions than the corresponding free acids and bases, butsalts having lower solubility than the corresponding free acids andbases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, such as i.v.or i.p., transdermal, rectal, vaginal, etc., or a form suitable foradministration by inhalation or insufflation.

For topical administration, the active compound(s), hydrate, solvate,N-oxide or pharmaceutically acceptable salt or prodrug(s) may beformulated as solutions, gels, ointments, creams, suspensions, etc. asare well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile, pyrogen-free water, buffer, dextrose solution, etc., beforeuse. To this end, the active compound(s) maybe dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients, such as:binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); and/or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such as:suspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s), hydrate, solvate, N-oxide,pharmaceutically acceptable salt or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,)dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5 20mg/ml); benzalkonium chloride (0.1 0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5 5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1 15 mg/ml); phenylethanol (1 4 mg/ml); and dextrose (20 50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH 5 to pH 7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation contains 20 mg/mLCompound or prodrug, 1% (v/v) Polysorbate 80 (TWEEN® 80), 50 mM citrateand/or 0.9% sodium chloride.

For ocular administration, the active compound(s) or prodrug(s) may beformulated as a solution, emulsion, suspension, etc. suitable foradministration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. Nos. 6,261,547;6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222;5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporatedherein by reference.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient maybe formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which areincorporated herein by reference.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents, such as dimethylsulfoxide (DMSO), may also beemployed, although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

C. Dosages

The pyrazole compound or combinations of pyrazole compounds willgenerally be used in an amount effective to achieve the intended result,for example, in an amount effective to treat or prevent a particularcondition. The pyrazole compound(s), or compositions thereof, can beadministered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. Therapeutic benefitmeans eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmatic attackor a reduction in the frequency or severity of asthmatic episodes.Therapeutic benefit also includes halting or slowing the progression ofthe disease, regardless of whether improvement is realized.

As known by those of ordinary skill in the art, the preferred dosage ofpyrazole compounds will also depend on various factors, including theage, weight, general health, and severity of the condition of thepatient or subject being treated. Dosage may also need to be tailored tothe sex of the individual and/or the lung capacity of the individual,when administered by inhalation. Dosage may also be tailored toindividuals suffering from more than one condition or those individualswho have additional conditions that affect lung capacity and the abilityto breathe normally, for example, emphysema, bronchitis, pneumonia, andrespiratory infections. Dosage, and frequency of administration of thepyrazole compound(s) or compositions thereof, will also depend onwhether the pyrazole compound(s) are formulated for treatment of acuteepisodes of a condition or for the prophylactic treatment of a disorder.A person or ordinary skill in the art will be able to determine theoptimal dose for a particular individual.

For prophylactic administration, the pyrazole compound, combinations ofpyrazole compounds, or compositions thereof, can be administered to apatient or subject at risk of developing one of the previously describedconditions. For example, if it is unknown whether a patient or subjectis allergic to a particular drug, the pyrazole compound, combinations ofpyrazole compounds, or compositions thereof, can be administered priorto administration of the drug to avoid or ameliorate an allergicresponse to the drug. Alternatively, prophylactic administration can beused to avoid or ameliorate the onset of symptoms in a patient diagnosedwith the underlying disorder. For example, a pyrazole compound(s), orcomposition thereof, can be administered to an allergy sufferer prior toexpected exposure to the allergen. A pyrazole compound, combinations ofpyrazole compounds, or compositions thereof, can also be administeredprophylactically to healthy individuals who are repeatedly exposed toagents known to one of the above-described maladies to prevent the onsetof the disorder. For example, a pyrazole compound, combinations ofpyrazole compounds, or compositions thereof, can be administered to ahealthy individual who is repeatedly exposed to an allergen known toinduce allergies, such as latex, in an effort to prevent the individualfrom developing an allergy. Alternatively, a pyrazole compound,combinations of pyrazole compounds, or compositions thereof, can beadministered to a patient suffering from asthma prior to partaking inactivities which trigger asthma attacks to lessen the severity of, oravoid altogether, an asthmatic episode.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in subjects can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ or EC₅₀ of the particular compound asmeasured in an in vitro assay. Dosages can be calculated to achieve suchcirculating blood or serum concentrations taking into account thebioavailability of the particular compound. Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pages 1-46, Pergamon Press, and the referencescited therein, provide additional guidance concerning effective dosages.

In some embodiments, the disclosed compounds have an EC₅₀ from greaterthan 0 to 20 M, such as from greater than 0 to 10 μM, from greater than0 to 5 μM, from greater than 0 to 1 M, from greater than 0 to 0.5 μM, orfrom greater than 0 to 0.1 μM.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Persons of ordinary skill in the art can adapt such information todetermine dosages suitable for human administration.

Dosage amounts of disclosed pyrazole compounds will typically be in therange of from about greater than 0 mg/kg/day, such as 0.0001 mg/kg/dayor 0.001 mg/kg/day or 0.01 mg/kg/day, up to at least about 100mg/kg/day. More typically, the dosage (or effective amount) may rangefrom about 0.0025 mg/kg to about 1 mg/kg administered at least once perday, such as from 0.01 mg/kg to about 0.5 mg/kg or from about 0.05 mg/kgto about 0.15 mg/kg. The total daily dosage typically ranges from about0.1 mg/kg to about 5 mg/kg or to about 20 mg/kg per day, such as from0.5 mg/kg to about 10 mg/kg per day or from about 0.7 mg/kg per day toabout 2.5 mg/kg/day. Dosage amounts can be higher or lower dependingupon, among other factors, the activity of the pyrazole compound, itsbioavailability, the mode of administration, and various factorsdiscussed above.

Dosage amount and dosage interval can be adjusted for individuals toprovide plasma levels of the pyrazole compound that are sufficient tomaintain therapeutic or prophylactic effect. For example, the compoundscan be administered once per day, multiple times per day, once per week,multiple times per week (e.g., every other day), one per month, multipletimes per month, or once per year, depending upon, amongst other things,the mode of administration, the specific indication being treated, andthe judgment of the prescribing physician. Persons of ordinary skill inthe art will be able to optimize effective local dosages without undueexperimentation.

Compositions comprising one or more of the disclosed pyrazole compoundstypically comprise from greater than 0 up to 99% of the pyrazolecompound, or compounds, and/or other therapeutic agent by total weightpercent. More typically, compositions comprising one or more of thedisclosed pyrazole compounds comprise from about 1 to about 20 totalweight percent of the pyrazole compound and other therapeutic agent, andfrom about 80 to about 99 weight percent of a pharmaceuticallyacceptable additive.

Preferably, the pyrazole compound, combinations of pyrazole compounds,or compositions thereof, will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of the pyrazolecompound can be determined using standard pharmaceutical procedures. Thedose ratio between toxic and therapeutic (or prophylactic) effect is thetherapeutic index. Pyrazole compounds that exhibit high therapeuticindices are preferred.

IV. Examples Example 1

Preparation of Amine 106:

2-(1H-Pyrazol-3-yl)pyridine (10 g) was suspended in concentratedsulfonic acid (30 mL), then fuming nitric acid (6.5 mL, 2 eq.) was addedto the solution dropwise while stirring. The reaction mixture wasstirred overnight at room temperature. It was quenched by pouring intoice-water (500 mL). The aqueous solution was neutralized by adding solidsodium carbonate, until pH reached around 8. White precipitate wascollected by filtration, washed with water and dried to give2-(4-nitro-1H-pyrazol-3-yl)pyridine 102 (13 g, 99% yield).

2-(4-nitro-1H-pyrazol-3-yl)pyridine 102 (2 g), and1-bromo-3-ethoxycyclobutane (90% trans isomer, 2 g) were suspended inTHF (20 mL) and DMF (10 mL). Sodium hydride (60% in oil, 670 mg, 1.5eq.) was added to the reaction. The reaction solution was heated at 100°C. for 3 days and then was evaporated. The residue was purified bycombiflash chromatography (EtOAc in hexanes=10-100%) to give product104.

Compound 104 was dissolved in EtOAc (100 mL) and charged with 10% Pd—Ccatalyst (200 mg). The reaction mixture was shaken under 40 psi hydrogenfor 1 hour. LC-MS indicated fully reduction of nitro group. The catalystwas filtered off through celite and washed with EtOAc (5×20 mL). Thefiltrate was concentrated to give amine 106 (1.4 g, 52% yield in twosteps).

Example 2 Exemplary synthesis of I-28:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

Compound 106 (700 mg), 5-bromo-2-furoic acid (622 mg, 1.2 eq.), and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) (1.54 g, 1.5 eq.) were dissolved inTHF (30 mL) and diisopropylethylamine (DIPEA) (0.7 mL, 1.5 eq.) wasadded to the solution. The reaction mixture was stirred at roomtemperature overnight and evaporated. The residue was purified bycombiflash chromatography (EtOAc in hexanes=10-100%) to give product 108(1 g, 87% yield).

Compound 108 (Ig), pyrazole-4-boronic acid (780 mg, 3 eq.), Na₂CO₃ (2.45g, 10 eq.) and PdCl₂ (dppf)₂ (250 mg) were stirred in dioxane (15 mL)and water (15 mL). The reaction mixture was heated at 100° C. overnight.LC-MS indicated fully conversion to the product. The reaction mixturewas evaporated and purified by combiflash chromatography (2.0 M NH₃/MeOHin DCM=0-20%) to give desired product I-28 (750 mg, 77% yield). ¹H NMR(300 MHz, DMSO) δ 13.25 (br, 1H), 11.63 (s, 1H), 8.72 (dd, J=6.0 Hz,1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.06 (d, J=6.9 Hz, 1H), 7.95 (m, 2H),7.42 (m, 1H), 7.26 (d, J=3.9 Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 4.60 (p,J=7.8 Hz, 1H), 3.83 (p, J=7.5 Hz, 1H), 3.40 (q, J=6.9 Hz, 2H), 2.79 (m,2H), 2.41 (m, 2H), 1.13 (t, J=6.9 Hz, 3H); LCMS: purity: 100%; MS (m/e):419.60 (MH+).

Example 3 Preparation of2-methyl-1-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)propan-2-ol (110)

Sodium hydride (1.657 g, 41.4 mmol) was weighed out and added to a dryreaction tube with magnetic stir bar and cooled to 0° C. This wascarefully suspended in 86 mL THF and the system was purged withnitrogen. 2-(4-Nitro-1H-pyrazol-3-yl)pyridine (3.928 g, 20.7 mmol) wasadded in 40 mL dimethylformamide followed by 7 mL dimethylformamidewashings. This was stirred 30 minutes at 0° C. followed by 30 minutes atroom temperature. It was then cooled back to 0° C. and isobutylene oxide(5.5 mL, 61.9 mmol) was added. The reaction was stirred warming to roomtemperature, heated 3 hours at 100° C. and stirred overnight at roomtemperature. The reaction was recharged with sodium hydride (0.445 g,11.2 mmol) and isobutylene oxide (1.8 mL, 20.3 mmol) and heated 2 hoursmore at 100° C. The reaction was quenched with water and concentrated todryness; the residue was partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. The aqueous layer was extracted threetimes more with ethyl acetate and the combined organic layer was washedwith brine and dried over sodium sulfate. Product solution was filtered,concentrated onto silica and purified by column chromatography. Afterdrying, 1.92 g of the title compound 110 was obtained in two batches(35% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.72-8.45 (m, 1H), 7.95-7.88(m, 1H), 7.71-7.65 (m, 1H), 7.51-7.43 (m, 1H), 4.89 (s, 1H), 4.14 (s,2H), 1.14 (s, 6H). m/z=263 (M+H)⁺.

Example 4 Preparation of1-(4-amino-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 112

2-Methyl-1-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)propan-2-ol 110(0.994 g, 3.8 mmol) was added to a Parr reaction bottle in 100 mL ethylacetate. This was put under nitrogen and charged with (wet) 10% Pd oncarbon (0.404 g, 0.2 mmol). This was run at 60 psi hydrogen overnight onthe Parr hydrogenator. The reaction was filtered through Celite withmethanol washings, concentrated onto silica and purified by columnchromatography. 0.723 g of the title compound 112 was obtained afterdrying on high vacuum (82% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (ddt, J=5.0, 1.9, 0.9 Hz, 1H),7.85-7.71 (m, 2H), 7.23-7.11 (m, 2H), 4.98 (s, 2H), 4.68 (s, 1H), 3.92(s, 2H), 1.08 (s, 6H). m/z=233 (M+H)⁺.

Example 5 Preparation of5-bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide114

5-Bromofuran-2-carboxylic acid (0.148 g, 0.77 mmol) was weighed out andadded to a flask with magnetic stir bar. This was dissolved in 33 mLdichloromethane and diisopropylethylamine (0.20 mL, 1.2 mmol) was addedfollowed by HATU (0.381 g, 1.0 mmol). This is stirred 30 minutes at roomtemperature and1-(4-amino-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 112(0.214 g, 0.92 mmol) was added in 13 mL dichloromethane solution. Thereaction was stirred overnight at room temperature. This wasconcentrated directly onto silica and purified by column chromatography.After drying, 0.358 g of the title compound 114 was obtained. (96% massbalance based on the aminopyrazole; hydroybutyl-related byproductsremained in the purified product. This was used directly.)

¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.65 (ddd, J=5.0, 1.8, 1.0Hz, 1H), 8.34 (s, 1H), 8.02-7.90 (m, 2H), 7.41 (ddd, J=7.2, 5.0, 1.6 Hz,1H), 7.27 (d, J=3.6 Hz, 1H), 6.88 (d, J=3.6 Hz, 1H), 4.77 (s, 1H), 4.11(s, 2H), 1.12 (s, 6H). m/z=405/407 (M+H)⁺ (bromine isotopes).

Example 6 Preparation of I-1:N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide

5-bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide114 (49 mg, 0.12 mmol) in 1.7 mL premixed 7/3 dimethoxyethane/ethanolsolution was added to a microwave reaction vial with magnetic stir bar.(1-Methyl-1H-pyrazol-4-yl)boronic acid (99 mg, 0.78 mmol) was weighedout and added to the vial. 2M aqueous sodium carbonate solution (0.41mL, 0.82 mmol) was added and the reaction was subjected to vigoroussubsurface nitrogen sparge. Pd[P(Ph)₃]₂Cl₂ (16 mg, 0.02 mmol) was added,the tube was sealed under nitrogen and then heated 30 minutes in themicrowave at 130° C. The reaction was worked up in the tube, firstdiluting with ethyl acetate. This was washed in succession with brine,1M aqueous sodium hydroxide solution, and brine, pipetting the aqueouslayer off the bottom of the tube. The aqueous was back-extracted twicewith ethyl acetate and the combined organic layer was dried in a vialover sodium sulfate. The product solution was filtered into anothervial, evaporated, and purified by preparative HPLC. After drying, 6 mgof the title compound I-1 was obtained as the TFA salt (10% yield; anadditional 12 mg less pure product was recovered).

¹H NMR (300 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.75 (ddd, J=5.0, 1.8, 0.9Hz, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 8.02 (dt, J=8.2, 1.2 Hz, 1H),7.99-7.92 (m, 1H), 7.90 (d, J=0.7 Hz, 1H), 7.43 (ddd, J=7.3, 4.9, 1.4Hz, 1H), 7.27 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 4.78 (s, 1H),4.11 (s, 2H), 3.95 (s, 3H), 1.12 (s, 6H). m/z=407 (M+H)⁺.

Example 7 Preparation of I-3:N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

5-bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide114 (0.289 g, 0.71 mmol) was weighed out and added to a microwavereaction tube with magnetic stir bar. Pyrazole-4-boronic acid (0.511 g,4.6 mmol) was added followed by 10 mL of a 7:3 dimethoxyethane/ethanolsolution. Sodium carbonate (0.514 g, 4.8 mmol) was dissolved in 2.42 mLwater and added to the reaction. This was subjected to vigoroussub-surface nitrogen sparge. Pd[P(Ph)₃]₂Cl₂ (60 mg, 0.09 mmol) wasadded, the tube was sealed under nitrogen and then heated 30 minutes inthe microwave at 130° C.

The solution was diluted into ethyl acetate and washed first with brine,then 1M aqueous sodium hydroxide, and again with brine before dryingover sodium sulfate. (The base wash was analyzed for desired product tomonitor potential loss to the aqueous layer.) Product solution wasfiltered, concentrated onto silica and purified by columnchromatography. 0.180 g of the title compound I-3 was obtained afterdrying (64% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 13.27 (s, 1H), 11.67 (s, 1H), 8.74 (ddd,J=5.0, 1.8, 0.9 Hz, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.10-7.80 (m, 3H),7.43 (ddd, J=7.3, 5.0, 1.4 Hz, 1H), 7.27 (d, J=3.5 Hz, 1H), 6.78 (d,J=3.5 Hz, 1H), 4.78 (s, 1H), 4.11 (s, 2H), 1.13 (s, 6H). m/z=393 (M+H)⁺.

Example 8 Preparation of I-4: tert-butyl4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate

5-bromo-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide(2.435 g, 6.0 mmol) was weighed out and added to a reaction tube withmagnetic stir bar. 1-Boc-pyrazole-4-boronic acid pinacol ester (3.535 g,12.0 mmol) was added and these were dissolved in 60 mLdimethylformamide. Cesium carbonate (3.916 g, 12.0 mmol) was weighed outand added and the reaction was subjected to vigorous sub-surfacenitrogen sparge. Pd(dppf)Cl₂.CH₂Cl₂ (0.491 g, 0.60 mmol) was addedfollowed by Ag₂O (1.391 g, 6.0 mmol). The tube was sealed under nitrogenand stirred overnight at room temperature. The reaction solution wasthen combined with a 0.64 mmol pilot reaction run under the sameconditions and filtered through Celite with ethyl acetate washings. Thefiltrate was concentrated to dryness and partitioned between ethylacetate and water. The aqueous layer is extracted three times more withethyl acetate and the combined organic layer is washed with brine anddried over sodium sulfate. Product solution is filtered, concentratedonto silica and purified by column chromatography. Pure fractions arecombined, concentrated and dried on high vacuum to give 2.2 g of thetitle compound I-4 (69% yield total).

¹H NMR (300 MHz, Chloroform-d) δ 11.83 (s, 1H), 8.69 (ddd, J=5.0, 1.9,1.0 Hz, 1H), 8.60-8.33 (m, 2H), 8.29-7.91 (m, 2H), 7.79 (ddd, J=8.1,7.5, 1.7 Hz, 1H), 7.28-7.21 (m, 2H), 6.62 (d, J=3.6 Hz, 1H), 4.35 (t,J=5.6 Hz, 2H), 3.86 (t, J=5.6 Hz, 2H), 3.51 (q, J=7.0 Hz, 2H), 1.72 (s,9H), 1.19 (t, J=7.0 Hz, 3H). m/z=493 (M+H)⁺.

Example 9 Preparation of2-bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide116

2-Bromothiazole-4-carboxylic acid (0.257 g, 1.2 mmol) was weighed outand added to a flask with a magnetic stir bar and taken up in 53 mLdichloromethane. Diisopropylethylamine (0.322 mL, 1.8 mmol) was addedfollowed by HATU (0.611 g, 1.6 mmol) and the reaction was stirred atroom temperature for 60 minutes.1-(4-Amino-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 112(0.344 g, 1.5 mmol) was added in 21 mL dichloromethane solution and thereaction was stirred overnight at room temperature. This wasconcentrated directly onto silica and purified by column chromatography.Product containing fractions were all found to containhydroxyazabenzotriazole as a contaminant. These were concentrated andpartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The aqueous layer was washed with ethyl acetate untilproduct was completely extracted. The combined organic layer was washedwith brine and dried over sodium sulfate. Filtration, concentration anddrying on high vacuum afforded 0.429 g of the pure title compound 114(82% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.70-8.57 (m, 1H), 8.42 (d,J=5.7 Hz, 2H), 8.06-7.87 (m, 2H), 7.39 (ddd, J=7.3, 4.9, 1.5 Hz, 1H),4.78 (s, 1H), 4.12 (s, 2H), 1.12 (s, 6H). m/z=422/424 (M+H)⁺ (bromineisotopes).

Example 10 Preparation of II-1:N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

2-Bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide116 (0.212 g, 0.50 mmol) was weighed out and added to a microwavereaction vial with magnetic stir bar. 1-Boc-pyrazole-4-boronic acidpinacol ester (0.944 g, 3.2 mmol) was added followed by 4.9 mLdimethoxyethane and 2.1 mL ethanol. Sodium carbonate (0.362 g, 3.4 mmol)was dissolved in 1.7 mL water and added to the reaction. The solutionwas subjected to vigorous sub-surface nitrogen sparge and Pd[P(Ph)₃]₂Cl₂(60 mg, 0.09 mmol) was added. The tube was sealed under nitrogen andheated 30 minutes in the microwave at 130° C. The solution was dilutedinto ethyl acetate and washed with saturated aqueous sodium bicarbonateand brine. The emulsified layer was back-extracted three times withethyl acetate and the combined organic layer was dried over sodiumsulfate. This was filtered, concentrated and purified by columnchromatography to give 0.160 g of the title compound II-1 after drying(78% yield).

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 12.21 (s, 1H), 8.77 (ddd,J=5.0, 1.8, 1.0 Hz, 1H), 8.45 (s, 1H), 8.44-8.05 (br s, 2H), 8.28 (s,1H), 8.03-7.90 (m, 2H), 7.42 (ddd, J=7.4, 4.9, 1.4 Hz, 1H), 4.79 (s,1H), 4.12 (s, 2H), 1.13 (s, 6H). m/z=410 (M+H)⁺.

Example 11 Preparation of II-11:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

Compound 106 (680 mg), 2-bromothiazole-4-carboxylic acid (658 mg, 1.2eq.), and HATU (1.5 g, 1.5 eq.) were dissolved in THF (30 mL) and DIPEA(0.7 mL, 1.5 eq.) was added to the solution. The reaction mixture wasstirred at room temperature overnight and evaporated. The residue waspurified by combiflash chromatography (EtOAc in hexanes=10-100%) to giveproduct 118 (980 mg, 83% yield).

Compound 118 (Ig), pyrazole-4-boronic acid (750 mg, 3 eq.), Na₂CO₃ (2.37g, 10 eq.) and PdCl₂(dppf)₂ (200 mg) were stirred in dioxane (15 mL) andwater (15 mL). The reaction mixture was heated at 100° C. overnight.LC-MS indicated fully conversion to the product. The reaction mixturewas evaporated and purified by combiflash chromatography (2.0 M NH3/MeOHin DCM=0-20%) to give desired product II-11 (700 mg, 72% yield). ¹H NMR(300 MHz, DMSO) δ 13.41 (br, 1H), 12.18 (s, 1H), 8.75 (d, J=4.5 Hz, 1H),8.46 (m, 2H), 8.27 (s, 1H), 8.06 (m, 2H), 7.93 (m, 1H), 7.42 (m, 1H),4.61 (p, J=8.1 Hz, 1H), 3.84 (p, J=6.9 Hz, 1H), 3.41 (q, J=6.9 Hz, 2H),2.80 (m, 2H), 2.44 (m, 2H), 1.13 (t, J=6.9 Hz, 3H); LCMS: purity: 100%;MS (m/e): 436.56 (MH+).

Example 12 Preparation of 4-nitro-3-(trifluoromethyl)-1H-pyrazole 120

72 mL concentrated sulfuric acid was added to a flask with magnetic stirbar and cooled to 0° C. 3-(trifluoromethyl)-pyrazole (12.070 g, 88.70mmol) was weighed out and added gradually. An addition funnel wasattached and charged with 90% fuming nitric acid (36 mL, 766 mmol). Thiswas added in dropwise at 0° C., and the reaction was stirred warming toroom temperature overnight. The reaction was then recharged with thesame nitric acid described above (19 mL, 404 mmol) at room temperatureand then stoppered. Stirring at room temperature continued overnight.

The reaction was poured over ice and neutalized by slow addition of 200g sodium carbonate. The pH was adjusted to 6 with 1M hydrochloric acidand the solution was extracted six times with ethyl acetate. Thecombined organic layer was dried over sodium sulfate, filtered, andconcentrated to an oil. This crystallized, and the solid was washed withminimal dichloromethane to give 3.250 g of the title compound 120 afterdrying. A second crop was isolated from the filtrate to give 1.752 gmore product (31% yield). Additional product remained in the filtrate.

¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H). m/z=180 (M−H)⁻.

Example 13 Preparation of3-(4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-one 122

Compound 120 (1.2356 g, 6.82 mmol) was dried in the tared reaction flaskand weighed. This was taken up in 22 mL tetrahydrofuran, and a magneticstir bar was added. 3-Bromocyclobutan-1-one (1.3837 g, 9.29 mmol) wasweighed into a tared vial and added to the reaction in 11 mLtetrahydrofuran solution. Potassium carbonate (1.417 g, 10.25 mmol) wasweighed out and added, and the reaction was stirred overnight at roomtemperature.

The reaction was next recharged with 3-bromocyclobutan-1-one (1.232 g,8.27 mmol) in 5 mL tetrahydrofuran and stirred overnight at roomtemperature. The mixture was then concentrated to remove THF, andpartitioned between ethyl acetate and water. The aqueous was extractedthree times more with ethyl acetate and the combined organic layer waswashed with brine and dried over sodium sulfate. This was filtered andconcentrated and it spontaneously crystallized. The solid was collected,washed with a minimal volume of dichloromethane and dried on high vacuumto give 677.2 mg of the title compound 122. A second crop isolated aftercrystallizing from the filtrate gave 432.2 mg more product 122 (65%yield). A 1D NOE experiment confirmed the N1 assignment of the pyrazolealkylation.

¹H NMR (300 MHz, DMSO-d₆) δ 9.44 (s, 1H), 5.34 (p, J=6.9 Hz, 1H), 3.67(d, J=6.7 Hz, 4H). Parent ion not observed.

Example 14 Preparation of(1s,3s)-3-(4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-ol124

Compound 122 (601.0 mg, 2.41 mmol) was dried in the tared reaction flaskand weighed. This was dissolved in 12 mL methanol, a magnetic stir barwas added, and the solution was cooled to 0° C. Sodium borohydride(137.9 mg, 3.64 mmol) was weighed out and added. The reaction wasstirred 2 hours at room temperature. After HPLC showed completion, thiswas concentrated onto silica and purified by column chromatography.After drying, 536.2 mg was obtained of the title compound 124 (88%yield).

¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 5.38 (d, J=6.7 Hz, 1H),4.63-4.46 (m, 1H), 4.06-3.89 (m, 1H), 2.83-2.70 (m, 2H), 2.42-2.29 (m,2H). m/z=252 (M+H)⁺.

Example 15 Preparation of1-((1s,3s)-3-ethoxycyclobutyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole126

Compound 124 (189.6 mg, 0.76 mmol) was transferred to a reaction tubewith magnetic stir bar in 5 mL dichloromethane. Silver triflate (586.2mg, 2.28 mmol) was weighed out and added, and 2,6-di-t-butylpyridine wasadded (0.58 mL, 2.62 mmol). The reaction was cooled to 0° C. and ethyliodide was added (0.20 mL, 2.50 mmol). The cooling bath was thenremoved, and it was stirred overnight at room temperature. This reactionwas combined with another (46.0 mg, 0.18 mmol) run under the sameconditions and filtered through Celite with dichloromethane washings.The filtrate was concentrated onto silica and purified by columnchromatography. After drying, 172.8 mg was obtained of the pure titlecompound 126 (66% yield).

¹H NMR (300 MHz, Chloroform-d) δ 8.33 (s, 1H), 4.46 (tt, J=9.0, 7.5 Hz,1H), 3.90 (tt, J=7.5, 6.4 Hz, 1H), 3.47 (q, J=7.0 Hz, 2H), 3.03-2.91 (m,2H), 2.57-2.44 (m, 2H), 1.23 (t, J=7.0 Hz, 3H). m/z=280 (M+H)⁺.

Example 16 Preparation of1-((1s,3s)-3-ethoxycyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-4-amine128

Compound 126 (231.4 mg, 0.83 mmol) was added to a Parr reaction bottlein 30 mL ethyl acetate. This was put under nitrogen and charged with(wet) 10% Pd on carbon (90.1 mg, 0.04 mmol). This was run at 50 psihydrogen for 5 hours on the Parr hydrogenator. The reaction was filteredthrough Celite with methanol washings and concentrated to dryness. HPLCshowed a complex mixture. 110.6 mg of this residue was dissolved in 10mL methanol. NiCl₂.x hydrate (400.1 mg, 1.68 mmol as the hexahydrate)was weighed out and added, and the mixture was cooled to 0° C. Sodiumborohydride (127.4 mg, 3.4 mmol) was weighed out and added slowly,portionwise. The reaction was allowed to stir overnight, warming to roomtemperature. This was filtered through Celite with methanol washings,concentrated onto silica and purified by column chromatography. Afterdrying, 76.2 mg was obtained of the title compound as an oil. (Theremainder of the residue recovered from the hydrogenation was reducedusing similar conditions and an additional 46.1 mg of the title compound128 was obtained—59% yield).

¹H NMR (300 MHz, Chloroform-d) δ 7.17 (s, 1H), 4.31 (tt, J=9.1, 7.5 Hz,1H), 3.82 (tt, J=7.6, 6.5 Hz, 1H), 3.44 (q, J=7.0 Hz, 2H), 2.93-2.80 (m,2H), 2.45-2.32 (m, 2H), 1.22 (t, J=7.0 Hz, 3H). m/z=250 (M+H)⁺.

Example 17 Preparation of2-bromo-N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide130

2-Bromothiazole-4-carboxylic acid (61.4 mg, 0.30 mmol) was weighed outand added to a flask with a magnetic stir bar and taken up in 12 mLdichloromethane. Diisopropylethylamine (0.077 mL, 0.44 mmol) was addedfollowed by HATU (145.4 mg, 0.38 mmol) and the reaction was stirred atroom temperature for 45 minutes. Compound 128 (73 mg, 0.29 mmol) wasadded in 5 mL dichloromethane solution and the reaction was stirredovernight at room temperature. This was concentrated directly ontosilica and purified by column chromatography. Concentrating, then dryingthe pure fractions on high vacuum afforded 71.0 mg of the title compound130 (55% yield).

¹H NMR (300 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.40 (s, 1H), 8.13 (s,1H), 4.52-4.32 (m, 1H), 3.86 (tt, J=7.6, 6.5 Hz, 1H), 3.46 (q, J=7.0 Hz,2H), 2.91 (dddd, J=9.3, 7.5, 6.5, 2.9 Hz, 2H), 2.52 (qdd, J=9.9, 5.2,2.6 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H). m/z=439/441 (M+H)⁺ (bromineisotopes).

Example 18 Preparation of II-62:N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

Compound 130 (67.7 mg, 0.15 mmol) was transferred to a microwavereaction tube with magnetic stir bar in solution (4.2 mL dimethoxyethaneand 3.0 mL ethanol). 1-Boc-pyrazole-4-boronic acid pinacol ester (290.6mg, 1.0 mmol) was weighed out and added. Sodium carbonate (109.0 mg, 1.0mmol) was weighed into a tared vial, dissolved in 1.0 mL water, andadded to the reaction. The solution was subjected to vigoroussub-surface nitrogen sparge. Pd[P(Ph)₃]₂Cl₂ (18.4 mg, 0.03 mmol) wasweighed out and added and the tube was sealed under nitrogen. This washeated 30 minutes at 100° C. in the microwave. The solution waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The aqueous layer was extracted three more times with ethylacetate and the combined organic layer was washed with brine and driedover sodium sulfate. This was filtered, concentrated and subjected tocolumn chromatography. The purest fractions were concentrated to give asolid which was triturated with acetonitrile and dried on high vacuum togive 8.0 mg of the title compound II-62. (Additional less pure materialwas recovered.)

¹H NMR (300 MHz, Chloroform-d) δ 9.44 (s, 1H), 8.45 (s, 1H), 8.12 (s,2H), 8.08 (s, 1H), 4.43 (ddd, J=16.6, 9.3, 7.5 Hz, 1H), 3.87 (tt, J=7.7,6.4 Hz, 1H), 3.47 (q, J=7.0 Hz, 2H), 2.92 (dddd, J=9.3, 7.5, 6.5, 3.3Hz, 2H), 2.54 (tdd, J=9.3, 7.7, 2.9 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H).m/z=427 (M+H)⁺.

Example 19 Preparation of2-bromo-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide132

Bromothiazole-4-carboxylic acid (416.2 mg, 2.00 mmol) was weighed outand added to a flask with a magnetic stir bar and taken up in 40 mLdichloromethane. Diisopropylethylamine (0.52 mL, 3.0 mmol) was addedfollowed by HATU (990.4 mg, 2.60 mmol) and the reaction was stirred atroom temperature for 45 minutes.1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (329.4 mg, 2.00 mmol)was added in 10 mL dichloromethane solution and the reaction was stirredovernight at room temperature. This was concentrated directly ontosilica and purified by column chromatography. After drying, 471.6 mg wasobtained of the title compound 132 (66% yield—additional less purematerial was recovered).

¹H NMR (300 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.29 (s, 1H), 8.13 (s,1H), 3.96 (s, 3H). m/z=355/357 (M+H)⁺ (bromine isotopes).

Example 20 Preparation of II-63:N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamidetrifluoroacetate salt

Compound 132 (100.0 mg, 0.28 mmol) and 1-Boc-pyrazole-4-boronic acidpinacol ester (531.4 mg, 1.80 mmol) were weighed out and added to amicrowave reaction tube with magnetic stir bar. 7.7 mL dimethoxyethaneand 5.5 mL ethanol were added. Sodium carbonate (200.2 mg, 1.89 mmol)was weighed into a tared vial, dissolved in 2.0 mL water, and added tothe reaction. The solution was subjected to vigorous sub-surfacenitrogen sparge. Pd[P(Ph)₃]₂Cl₂ (34.4 mg, 0.05 mmol) was weighed out andadded and the tube was sealed under nitrogen. This was heated 30 minutesat 100° C. in the microwave. This was concentrated to removedimethoxyethane and ethanol and extracted four times with ethyl acetate.The combined organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated. This was purified by preparativeHPLC to give compound II-64. After drying, 54.3 mg was obtained of thetitle compound II-63 as a trifluoroacetic acid salt.

¹H NMR (300 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.32 (s, 1H), 8.25 (s, 2H),3.95 (s, 3H). m/z=343 (M+H)⁺.

Example 21 Preparation of(1s,3s)-3-(4-amino-3-(3-fluoropyridin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol134

(1s,3s)-3-(3-(3-fluoropyridin-2-yl)-4-nitro-1H-pyrazol-1-yl)cyclobutan-1-ol(1.070 g, 3.85 mmol) was weighed out and added to a flask with magneticstir bar, and dissolved in 98 mL ethyl acetate. This was put undernitrogen and charged with (wet) 10% Pd on carbon (117.8 mg, 0.014 mmol).After thoroughly purging with nitrogen, this was stirred for 3 hoursunder a balloon of hydrogen. The reaction was then filtered throughCelite with excess ethyl acetate washings. The filtrate was concentratedand dried to give quantitative recovery of the title compound 134 as afoam. This was used in the next reaction without further purification.

¹H NMR (300 MHz, DMSO-d₆) δ 8.47-8.31 (m, 1H), 7.79-7.62 (m, 1H),7.35-7.22 (m, 2H), 5.26 (d, J=6.6 Hz, 1H), 4.94 (s, 2H), 4.34-4.18 (m,1H), 3.93 (td, J=7.4, 6.0 Hz, 1H), 2.71 (dtd, J=8.7, 7.1, 3.0 Hz, 2H),2.27 (qd, J=8.7, 2.9 Hz, 2H). m/z=249 (M+H)⁺.

Example 22 Preparation of2-bromo-N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide136

Compound 134 (0.96 g, 3.85 mmol) was dried in the tared reaction flaskand weighed. This was dissolved in 30 mL dichloromethane, and 10 mLdimethylformamide was added along with a magnetic stir bar.

2-Bromothiazole-4-carboxylic acid (800.6 mg, 3.85 mmol) was weighed outand added. Diisopropylethylamine (1.0 mL, 5.7 mmol) was added followedby HATU (1.901 g, 5.00 mmol) and the reaction was stirred at roomtemperature overnight. This was concentrated directly onto silica andpurified by column chromatography. Concentrating, then drying the purefractions on high vacuum afforded 1.158 g of the title compound 136 (69%yield).

¹H NMR (300 MHz, DMSO-d₆) δ 12.14 (s, 1H), 8.57-8.48 (m, 2H), 8.44 (s,1H), 7.91 (ddd, J=11.5, 8.4, 1.3 Hz, 1H), 7.52 (ddd, J=8.4, 4.6, 3.8 Hz,1H), 5.34 (d, J=6.9 Hz, 1H), 4.52 (tt, J=9.1, 7.3 Hz, 1H), 4.05-3.91 (m,1H), 2.86-2.72 (m, 2H), 2.39 (qd, J=8.6, 2.8 Hz, 2H). m/z=438/440 (M+H)⁺(bromine isotopes).

Example 23 Preparation of II-65:N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

Compound 136 (0.497 g, 1.13 mmol) was transferred to a microwavereaction tube with magnetic stir bar in solution (13 mL dimethoxyethaneand 5.5 mL ethanol). 1-Boc-pyrazole-4-boronic acid pinacol ester (1.334g, 4.53 mmol) was weighed out and added. Sodium carbonate (0.480 g, 4.53mmol) was weighed into a tared vial, dissolved in 4.5 mL water, andadded to the reaction. The solution was subjected to vigoroussub-surface nitrogen sparge. Pd[P(Ph)₃]₂Cl₂ (79.6 mg, 0.11 mmol) wasweighed out and added and the tube was sealed under nitrogen. This washeated 90 minutes at 100° C. in the microwave. This was concentrated toremove dimethoxyethane and ethanol and extracted four times with ethylacetate. However, there was substantial undissolved solid. This wascollected and washed repeatedly with methanol. After drying, this gave174.0 mg of the title compound at 90% purity.

The combined organic layer from the extraction was washed with brine,dried over sodium sulfate, filtered, and combined with the methanolwashings of the precipitated solid. The solution was concentrated ontosilica and purified by column chromatography. Concentration of purefractions gave a solid which was triturated with minimaldichloromethane. After drying, 169.2 mg was obtained of the pure titlecompound II-65.

¹H NMR (300 MHz, DMSO-d₆) δ 13.43 (s, 1H), 12.09 (s, 1H), 8.66 (dt,J=4.6, 1.4 Hz, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.11 (s,1H), 7.91 (ddd, J=11.5, 8.4, 1.3 Hz, 1H), 7.54 (ddd, J=8.4, 4.6, 3.8 Hz,1H), 5.34 (d, J=6.9 Hz, 1H), 4.61-4.42 (m, 1H), 3.98 (h, J=7.4 Hz, 1H),2.80 (dtd, J=9.6, 6.9, 2.8 Hz, 2H), 2.47-2.33 (m, 2H). m/z=426 (M+H)⁺.

Example 24 Preparation of2-(4-nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-3-yl)pyridine138

A stirring suspension of 2-(4-nitro-1H-pyrazol-3-yl)pyridine (950 mg,5.00 mmol), 1,4-dioxaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (1.69g, 5.41 mmol) and Cs₂CO₃ (2.44 g, 7.50 mmol) in anhydrous THF:DMF (15mL, 4:1, v/v) was heated to 100° C. and stirred for 16 hours. Thereaction mixture was diluted in water (50 mL), extracted with EtOAc(3×50 mL), the organic layer was washed with brine (50 mL), dried overMgSO₄, concentrated and column chromatography (0-100% EtOAc in hexane,gradient) gave compound 138 as a light brown semisolid (910 mg, 55.14%).MS (m/e): 330.34 (MH+).

Example 25 Preparation of4-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)cyclohexan-1-one 140

To a stirring solution of compound 138 (910 mg, 2.75 mmol) inacetone:H₂O (20 mL, 1:1, v/v) was added pyridinium p-tolulene sulfonate(1.38 g, 5.50 mmol) and the reaction mixture was heated to 80° C. andstirred for 16 hours. Acetone was evaporated in vacuo, the aqueous layerwas quenched with NaOH to pH=8, extracted with EtOAc (3×50 mL), theorganic layer was washed with brine (50 mL), dried over MgSO₄,concentrated and column chromatography (0-100% MeOH in DCM, gradient)gave compound 140 as a dark brown oil (600 mg, 76.08%). MS (m/e): 286.29(MH+).

Example 26 Preparation of(trans)-4-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol 142

NaBH₄ (20 mg, 0.524 mmol) was added to a stirring solution of 2 (00 mg,2.10 mmol) in MeOH (10 mL) at 0° C., stirred for 0.5 hours, concentratedand column chromatography (0-100% MeOH (1M NH₃ solution) in DCM,gradient) afforded the product 142 as a viscous oil (362 mg, 60%).

¹H NMR (300 MHz, Chloroform-d) δ 8.77 (d, J=4.8 Hz, 1H), 8.29 (s, 1H),7.84 (m, 2H), 7.36 (m, 1H), 4.24 (m, 1H), 3.76 (m, 1H), 3.46 (s, 1H),2.14 (m, 8H).

LCMS: purity: 87.43%. MS (m/e): 288.31 (MH+).

Example 27 Preparation of2-(1-((trans)-4-ethoxycyclohexyl)-4-nitro-1H-pyrazol-3-yl)pyridine 146

NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol) was added to astirring solution of compound 142 (360 mg, 1.25 mmol) and iodoethane(200 μL, 2.50 mmol) in anhydrous DMF (8 mL) at −20 OC. The reactionmixture was allowed to warm to room temperature for 2 hours. Thereaction mixture was diluted in water (40 mL), extracted with EtOAc(3×50 mL), the organic layer was washed with brine (30 mL), dried overMgSO₄, concentrated, and column chromatography (0-100% EtOAc in hexane,gradient) afforded the product 146 as viscous oil (296 mg, 74.93%). MS(m/e): 316.36 (MH+).

Example 28 Preparation of1-((trans)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-amine 148

A solution of compound 146 (290 g, 0.917 mmol) in EtOAc (10 mL) withPd/C (10% wt, 50 mg) was hydrogenated under 50 psi H₂ (g) for 12 hours,filtered through celite and concentrated to give compound 148 as aviscous oil (230 mg, 87.61%). MS (m/e): 286.38 (MH+).

Example 29 Preparation of2-bromo-N-(1-((trans)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide150

HATU (458 mg, 1.20 mmol) was added to a stirring solution of2-bromothiazole-4-carboxylic acid (184 mg, 0.883 mmol) and DIPEA (280μL, 1.61 mmol) in anhydrous THF (4 mL) at room temperature for 10minutes, followed by addition of a solution of compound 148 (230 mg,0.803 mmol) in anhydrous THF (4 mL). After 1 hour, the reaction mixturewas diluted in water (10 mL), extracted with EtOAc (3×20 mL), theorganic layer was washed with brine (20 mL), dried over MgSO₄,concentrated, and column chromatography (0-100% EtOAc in hexane,gradient) afforded the product 150 as a semisolid, which was usedwithout further purification. Assumed quantitative yield. MS (m/e):476.39 (MH+).

Example 30 Preparation of II-145:N-(1-((trans)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

A mixture of crude compound 150 (0.803 mmol), 1H-pyrazole-4-boronic acid(180 mg, 1.61 mmol), Pd(dppf)Cl₂ (65.6 mg, 0.080 mmol), 2 M Na₂CO₃ (1.61mL, 3.21 mmol) and anhydrous 1,4-dioxane (10 mL) was heated at 105° C.and stirred for 16 hours. The reaction mixture was cooled to roomtemperature, diluted in water (20 mL), extracted with EtOAc (3×30 mL),the organic layer was washed with brine (20 mL), dried over MgSO₄,concentrated, and column chromatography (0-100% EtOAc in hexane,gradient) gave a semisolid, which was submitted for analyticalpurification, followed by lyophilization to afford the title compoundII-145 as a white fluffy solid (75 mg, 20.15%).

¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 12.18 (s, 1H), 8.74 (d, J=4.8Hz, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.97(m, 2H), 7.39 (t, J=6.9 Hz, 1H), 4.29 (t, J=11.7 Hz, 1H), 3.47 (td,J=7.1, 5.8 Hz, 2H), 3.35 (t, J=11.7 Hz, 1H), 2.09 (d, J=11.6 Hz, 4H),1.87 (q, J=11.8 Hz, 2H), 1.35 (q, J=11.2 Hz, 2H), 1.10 (t, J=6.9 Hz,3H). LCMS: purity: 100%. MS (m/e): 463.56 (MH+).

The following exemplary compounds were prepared using the methods ofExamples 1-23. Characterization data for these additional compounds areprovided below.

I-5:N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (DMSO d₆, 300 MHz): δ 11.66 (s, 1H), 8.75-8.73 (m, IH), 8.38 (s,IH), 8.12-7.92 (m, 4H), 7.45-7.41 (m, 1H), 7.29-7.27 (m, IH), 6.79-6.78(m, IH), 4.37 (t, J=6.7 Hz, 2H), 3.75 (t, J=6.7 Hz, 2H), 3.27 (s, 3H);LCMS (m/z): 379.52 (MH⁺).

I-6:N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamideFormic Acid

LCMS (m/z): 393.49 (MH⁺).

I-7:N-(1-(2-methoxyethyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

LCMS (m/z): 380.54 (MH⁺).

I-8:N-(1-(2-methoxyethyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (DMSO d₆, 300 MHz): δ 11.09 (s, 1H), 8.93 (d, J=3.3 Hz, 2H), 8.46(s, IH), 7.49 (t, J=6.7 Hz, 1H), 7.33 (d, J=3.3 Hz, 1H), 6.70 (d, J=3.3Hz, 1H), 4.40 (t, J=6.7 Hz, 2H), 3.76 (t, J=6.7 Hz, 2H), 3.27 (s, 3H),2.50 (s, 3H); LCMS (m/z): 394.45 (MH⁺).

I-9:N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (DMSO d₆, 300 MHz): δ 11.43 (s, 1H), 8.67-8.64 (m, 1H), 8.41 (s,IH), 8.05-7.91 (m, 3H), 7.43-7.29 (m, 1H), 7.30 (d, J=3.3 Hz, 1H), 6.69(d, J=3.3 Hz, 1H), 4.37 (t, J=6.7 Hz, 2H), 3.75 (t, J=6.7 Hz, 2H), 3.27(s, 3H), 2.53 (s, 3H); LCMS (m/z): 393.53 (MH⁺).

I-10: di-tert-butyl((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)phosphate

¹H NMR (CDCl₃, 300 MHz): δ 11.86 (s, 1H), 8.77-8.75 (m, 1H), 8.41 (s,IH), 8.12-8.07 (m, 2H), 7.98 (s, 1H), 7.80-7.74 (m, 1H), 7.23 (d, J=6.7Hz, 1H), 6.52 (d, J=3.3 Hz, 1H), 5.94 (d, J=13.3 Hz, 2H), 4.34 (t, J=6.7Hz, 2H), 3.83 (t, J=6.7 Hz, 2H), 3.37 (s, 3H), 1.44 (s, 18H); LCMS(m/z): 601.70 (MH⁺).

I-11: tert-butyl((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)hydrogen phosphate

¹H NMR (CDCl₃, 300 MHz): δ 11.61 (s, 1H), 8.51-8.49 (m, 1H), 8.26 (s,IH), 8.00-7.93 (m, 2H), 7.77 (s, 1H), 7.66-7.58 (m, 2H), 7.14-7.10 (m,1H), 7.03 (d, J=3.3 Hz, 1H), 6.37 (d, J=3.3 Hz, 1H), 5.79-5.70 (m, 2H),4.26 (t, J=6.7 Hz, 2H), 3.78 (t, J=6.7 Hz, 2H), 3.34 (s, 3H), 1.27 (s,9H); LCMS (m/z): 545.74 (MH⁺).

I-12:(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

¹H NMR (DMSO d₆, 300 MHz): δ 11.71 (s, 1H), 8.86-8.84 (m, 1H), 8.38-8.37(m, 2H), 8.06-7.92 (m, 3H), 7.43-7.39 (m, 1H), 7.30 (d, J=3.3 Hz, 1H),6.88 (d, J=3.3 Hz, 1H) 5.92 (d, J=10.0 Hz, 2H), 4.38 (t, J=6.7 Hz, 2H),3.75 (t, J=6.7 Hz, 2H), 3.27 (s, 3H); LCMS (m/z): 489.51 (MH⁺).

I-13:N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide

LCMS (m/z): 447.67 (MH⁺).

I-14: sodium(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methylphosphate

¹H NMR (D₂O, 300 MHz): δ 7.90-7.86 (m, 2H), 7.48 (s, 1H), 7.45 (t,J=10.0 Hz, 1H), 7.28-7.23 (m, 2H), 6.96-6.92 (m, 1H), 6.65 (d, J=3.3 Hz,1H), 6.23 (d, J=3.3 Hz, 1H), 5.64 (d, J=3.3 Hz, 2H), 4.02 (t, J=6.7 Hz,2H), 3.75 (t, J=6.7 Hz, 2H), 3.35 (s, 3H); LCMS (m/z): 489.24 (MH⁺).

I-15:N-(1-(2-hydroxyethyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (DMSO d₆, 300 MHz): δ 11.31 (s, 1H), 8.98 (d, J=3.3 Hz, 2H), 8.43(s, 1H), 7.50 (t, J=6.7 Hz, 1H), 7.31 (d, J=3.3 Hz, 1H), 6.79 (d, J=6.7Hz, 1H), 4.98 (t, J=6.7 Hz, 1H), 4.27 (t, J=6.7 Hz, 2H), 3.84-3.78 (m,1H); LCMS (m/z): 366.55 (MH⁺).

I-16:N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

LCMS (m/z): 423.60 (MH⁺).

I-17:N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamidehydrochloride salt

¹H NMR (DMSO d₆, 300 MHz): δ 11.65 (s, 1H), 8.75-8.73 (m, 1H), 8.40 (s,1H), 8.12 (s, 2H), 8.04-7.93 (m, 2H), 7.29 (d, J=3.3 Hz, 1H), 6.79 (d,J=6.7 Hz, 1H), 4.37 (t, J=6.7 Hz, 1H), 3.84 (t, J=6.7 Hz, 2H), 3.56-3.53(m, 2H), 3.44-3.41 (m, 2H), 3.22 (s, 3H); LCMS (m/z): 423.62 (MH⁺).

I-18:N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (DMSO d₆, 300 MHz): δ 11.40 (s, 1H), 8.63-8.61 (m, 1H), 8.40 (s,1H), 8.02-7.89 (m, 3H), 7.40-7.36 (m, 1H), 7.27 (d, J=3.3 Hz, 1H), 6.66(d, J=3.3 Hz, 1H), 4.34 (t, J=6.7 Hz, 1H), 3.81 (t, J=6.7 Hz, 2H),3.53-3.50 (m, 2H), 3.41-3.37 (m, 2H), 3.18 (s, 3H), 2.47 (s, 3H); LCMS(m/z): 437.66 (MH⁺).

I-19: 1-(isobutyryloxy)ethyl4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate

¹H NMR (DMSO d₆, 300 MHz): δ 11.72 (s, 1H), 8.80 (s, 1H), 8.75-8.73 (m,1H), 8.38 (d, J=3.3 Hz, 2H), 8.05-7.94 (m, 2H), 7.44-7.40 (m, 1H), 7.34(d, J=3.3 Hz, 1H), 7.10 (d, J=3.3 Hz, 1H), 7.05-7.00 (m, 1H), 4.38 (t,J=6.7 Hz, 1H), 3.76 (t, J=6.7 Hz, 2H), 3.27 (s, 3H), 2.63 (s, J=3.3 Hz,1H), 1.66 (d, J=6.7 Hz, 3H), 1.11 (d, J=6.7 Hz, 6H); LCMS (m/z): 537.68(MH⁺).

I-20: tert-butyl(S)-(1-(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

¹H NMR (DMSO d₆, 300 MHz): δ 11.71 (s, 1H), 8.92 (s, 1H), 8.76-8.74 (m,1H), 8.40 (s, 2H), 8.05-7.93 (m, 2H), 7.50-7.41 (m, 2H), 7.36 (d, J=3.3Hz, 1H), 7.12 (d, J=3.3 Hz, 1H), 5.25-5.20 (m, 1H), 4.38 (t, J=6.7 Hz,1H), 3.76 (t, J=6.7 Hz, 2H), 3.27 (s, 3H), 1.84 (s, 1H), 1.39 (s, 9H),0.93 (s, J=6.7 Hz, 6H); LCMS (m/z): 578.76 (MH⁺).

I-21: 1-methylcyclopropyl4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate

¹H NMR (DMSO d₆, 300 MHz): δ 11.71 (s, 1H), 8.75-8.72 (m, 2H), 8.39 (s,1H), 8.31 (s, 1H), 8.05-7.94 (m, 2H), 7.45-7.41 (m, 1H), 7.33 (d, J=3.3Hz, 1H), 7.06 (d, J=6.7 Hz, 1H), 4.38 (t, J=6.7 Hz, 1H), 3.76 (t, J=6.7Hz, 2H), 3.27 (s, 3H), 1.69 (s, 3H), 1.16 (t, J=6.7 Hz, 1H), 0.86 (t,J=6.7 Hz, 2H); LCMS (m/z): 477.66 (MH⁺).

I-22: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate

¹H NMR (DMSO d₆, 300 MHz): δ 11.73 (s, 1H), 8.71-8.70 (m, 1H), 8.64 (s,1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.04-7.92 (m, 2H), 7.40-7.33 (m, 1H),7.21 (d, J=6.7 Hz, 1H), 7.07 (d, J=3.3 Hz, 1H), 6.83 (d, J=6.7 Hz, 1H),4.47 (s, 2H), 4.38 (t, J=6.7 Hz, 1H), 3.75 (t, J=6.7 Hz, 2H), 3.67 (s,3H), 3.27 (s, 3H), 1.61 (s, 6H); LCMS (m/z): 615.79 (MH⁺).

I-23:5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (DMSO d₆, 300 MHz): δ 13.27 (s, 1H), 11.67 (s, 1H), 8.75-8.73 (m,1H), 8.42 (s, 1H), 8.26 (s, 1H), 8.06-7.95 (m, 3H), 7.45-7.43 (m, 1H),7.28 (d, J=3.3 Hz, 1H), 6.79 (d, J=3.3 Hz, 1H), 4.53 (s, br, 1H),4.02-3.98 (m, 2H), 3.53-3.45 (m, 2H), 2.04 (s, br, 4H); LCMS (m/z):405.56 (MH⁺).

I-24:5-(5-nitro-1H-pyrrol-3-yl)-N-(1-(propoxymethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

LCMS (m/z): 437.54 (MH⁺).

I-25:N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.20 (br, 1H), 11.61 (s, 1H), 8.70 (d,J=6.6 Hz, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.8.07 (d, J=9.0 Hz, 1H),7.96-7.90 (m, 2H), 7.42-7.38 (m, 1H), 7.23 (d, J=3.6 Hz, 1H), 6.72 (d,J=3.6 Hz, 1H), 5.66 (p, J=6.6 Hz, 1H), 4.94-4.87 (m, 4H); LCMS: purity:100%; MS (m/e): 377.47 (MH+).

I-26:5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.76 (d, J=7.8 Hz, 1H), 8.48(s, 1H), 8.18 (s, 1H), 8.11 (d, J=10.2 Hz, 1H), 7.97 (dt, J=7.5, 1.8 Hz,1H), 7.89 (s, 1H), 7.45 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 7.28 (d, J=3.6Hz, 1H), 6.75 (d, J=3.6 Hz, 1H), 5.71 (p, J=6.9 Hz, 1H), 4.97-4.94 (m,4H), 3.94 (s, 3H); LCMS: purity: 100%; MS (m/e): 391.48 (MH+).

I-27:N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 11.64 (s, 1H), 8.73 (d, J=4.8Hz, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.98-7.92(m, 2H), 7.42 (m, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.9 Hz, 1H),5.06 (p, J=6.0 Hz, 1H), 4.28 (m, 1H), 3.40 (q, J=6.9 Hz, 2H), 2.74-2.66(m, 2H), 1.14 (t, J=6.9 Hz, 3H); LCMS: purity: 91.98%; MS (m/e): 419.60(MH+).

I-29:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.41(s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.93 (m, 1H), 7.39 (m, 1H), 7.28 (d,J=3.6 Hz, 1H), 6.67 (d, J=3.6 Hz, 1H), 4.60 (p, J=6.9 Hz, 1H), 3.83 (p,J=7.5 Hz, 1H), 3.40 (q, J=6.9 Hz, 2H), 2.79 (m, 2H), 2.41 (m, 2H), 1.13(t, J=7.2 Hz, 3H); LCMS: purity: 91.56%; MS (m/e): 433.52 (MH+).

I-30:5-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 12.99 (br, 1H), 11.43 (s, 1H), 8.67 (d, 1H),8.51 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.97 (t, J=8.4 Hz, 1H), 7.85 (s,1H), 7.43 (d, J=5.7 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 6.67 (d, J=3.9 Hz,1H), 5.70 (p, J=6.9 Hz, 1H), 4.96-4.92 (m, 4H), 2.54 (s, 3H); LCMS:purity: 88.90%; MS (m/e): 391.51 (MH+).

I-31:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.74 (d, J=5.4 Hz, 1H), 8.39(s, 1H), 8.18 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.94 (td, J=7.8, 1.8 Hz,1H), 7.88 (s, 1H), 7.43 (ddd, J=7.5, 5.0, 1.3 Hz, 1H), 7.26 (d, J=3.6Hz, 1H), 6.75 (d, J=3.6 Hz, 1H), 4.60 (p, J=8.4 Hz, 1H), 3.94 (s, 3H),3.83 (p, J=6.6 Hz, 1H), 3.40 (q, J=6.9 Hz, 2H), 2.84-2.75 (m, 2H),2.46-2.36 (m, 2H), 1.13 (t, J=6.9 Hz, 3H); LCMS: purity: 91.65%; MS(m/e): 433.57 (MH+).

I-32:N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.23 (br, 1H), 11.64 (s, 1H), 8.72 (d,J=5.1 Hz, 1H), 8.41 (s, 1H), 8.25 (br, 1H), 8.04 (d, J=8.4 Hz, 1H),7.98-7.92 (m, 2H), 7.40 (m, 1H), 7.27 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.3Hz, 1H), 5.31 (d, J=6.6 Hz, 1H), 4.42 (m, 1H), 3.96 (q, J=7.2 Hz, 1H),2.79 (m, 2H), 2.40 (m, 2H); LCMS: purity: 92.77%; MS (m/e): 391.56(MH+).

I-34:N-(1-((1,3-cis)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

LCMS: purity: 94.57%; MS (m/e): 418.59 (MH+).

I-35:(4-(5-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methylphosphate bis-sodium salt

1H NMR (300 MHz, Deuterium Oxide) δ 7.77 (d, 1H), 7.50 (m, 3H), 7.16 (m,2H), 6.94 (m, 1H), 6.50 (d, 1H), 6.03 (d, J=3.3 Hz, 1H), 5.50 (d, J=9.9Hz, 2H), 4.07 (t, J=8.1 Hz, 1H), 3.86 (t, J=6.9 Hz, 1H), 3.44 (q, J=6.9Hz, 2H), 2.73 (m, 2H), 2.10 (q, J=9.3 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H);LCMS: purity: 98.27%; MS (m/e): 529.62 (MH+).

I-37:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamideformic acid salt

MS (ESI) (m/z): 393 [M+H]⁺

I-38:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.65 (s, 1H), 8.74 (d, J=4.9 Hz, 1H), 8.39(s, 1H), 8.11 (s, 2H), 8.02 (d, J=7.9 Hz, 1H), 7.94 (td, J=7.8, 1.8 Hz,1H), 7.42 (t, J=6.1 Hz, 1H), 7.28 (d, J=3.6 Hz, 1H), 6.78 (d, J=3.6 Hz,1H), 4.36 (t, J=5.3 Hz, 2H), 3.79 (t, J=5.3 Hz, 2H), 3.45 (q, J=7.1 Hz,3H), 1.08 (t, J=7.0 Hz, 3H); MS (ESI) (m/z): 393 [M+H]⁺.

I-39:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.77-8.71 (m, 1H), 8.39 (s,1H), 8.24 (d, J=0.7 Hz, 1H), 8.02 (dt, J=8.1, 1.2 Hz, 1H), 7.98-7.91 (m,1H), 7.91 (d, J=0.8 Hz, 1H), 7.42 (ddd, J=7.3, 5.0, 1.4 Hz, 1H), 7.27(d, J=3.6 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 4.24(q, J=7.3 Hz, 2H), 3.79 (t, J=5.3 Hz, 2H), 3.45 (q, J=7.0 Hz, 2H), 1.45(t, J=7.3 Hz, 3H), 1.08 (t, J=7.0 Hz, 3H); MS (ESI) (m/z): 421 [M+H]⁺.

I-41:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 11.47 (s, 1H), 8.63 (ddd, J=5.1, 1.8, 1.0Hz, 1H), 8.50 (d, J=1.2 Hz, 1H), 8.43 (s, 1H), 8.01 (dt, J=8.0, 1.1 Hz,1H), 7.92 (td, J=7.7, 1.7 Hz, 1H), 7.38 (ddd, J=7.3, 5.0, 1.4 Hz, 1H),7.34 (dd, J=3.6, 0.6 Hz, 1H), 6.80 (d, J=3.6 Hz, 1H), 4.36 (t, J=5.3 Hz,2H), 3.79 (t, J=5.3 Hz, 2H), 3.45 (q, J=7.0 Hz, 2H), 1.08 (t, J=7.0 Hz,3H); MS (ESI) (m/z): 461 [M+H]⁺.

I-43:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.73 (ddd, J=5.0, 1.7, 1.0Hz, 1H), 8.39 (s, 1H), 8.25 (d, J=0.7 Hz, 1H), 8.02 (dt, J=8.0, 1.2 Hz,1H), 7.98-7.93 (m, 1H), 7.93-7.89 (m, 1H), 7.40 (ddd, J=7.3, 5.0, 1.4Hz, 1H), 7.27 (d, J=3.6 Hz, 1H), 6.75 (d, J=3.5 Hz, 1H), 4.35 (t, J=5.3Hz, 2H), 4.23 (t, J=7.2 Hz, 2H), 3.78 (t, J=5.3 Hz, 2H), 3.45 (q, J=7.0Hz, 2H), 1.74 (q, J=6.9 Hz, 2H), 1.51 (dp, J=13.4, 6.7 Hz, 1H), 1.08 (t,J=7.0 Hz, 3H), 0.93 (d, J=6.6 Hz, 6H); MS (ESI) (m/z): 463 [M+H]⁺.

I-45:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.39 (s, 1H), 8.19 (d, J=0.7Hz, 1H), 8.02 (dt, J=8.1, 1.2 Hz, 1H), 7.94 (ddd, J=8.0, 7.3, 1.7 Hz,1H), 7.90 (s, 1H), 7.70-7.47 (m, 1H), 7.43 (ddd, J=7.3, 4.9, 1.4 Hz,1H), 7.28 (dd, J=3.6, 0.5 Hz, 1H), 6.83-6.70 (m, 1H), 4.36 (t, J=5.3 Hz,2H), 3.95 (s, 3H), 3.79 (t, J=5.3 Hz, 2H), 3.45 (q, J=7.0 Hz, 2H), 1.08(t, J=7.0 Hz, 3H); MS (ESI) (m/z): 407 [M+H]⁺.

I-47:5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.40-12.84 (m, 1H), 11.67 (s, 1H), 8.75(dt, J=5.0, 1.3 Hz, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.16-7.81 (m, 3H),7.42 (ddd, J=7.5, 5.0, 1.3 Hz, 1H), 7.27 (d, J=3.6 Hz, 1H), 6.78 (d,J=3.5 Hz, 1H); MS (ESI) (m/z): 321 [M+H]⁺.

I-48:5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamideformic acid salt

MS (ESI) (m/z): 489 [M+H]⁺.

I-50:N-(2-(2-methoxyethoxy)ethyl)-5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamideformic acid salt

MS (ESI) (m/z): 627 [M+H]⁺.

I-52:5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamideformic acid salt

MS (ESI) (m/z): 525 [M+H]⁺.

I-54:(4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

¹H NMR (300 MHz, DMSO-d₆) δ 11.70 (s, 1H), 8.83 (dt, J=5.0, 1.3 Hz, 1H),8.36 (d, J=8.6 Hz, 2H), 8.09-7.86 (m, 3H), 7.49-7.33 (m, 1H), 7.28 (d,J=3.6 Hz, 1H), 6.86 (d, J=3.6 Hz, 1H), 5.88 (d, J=10.9 Hz, 2H), 4.35 (t,J=5.3 Hz, 2H), 3.78 (t, J=5.3 Hz, 2H), 3.45 (dd, J=14.0, 7.0 Hz, 2H),1.08 (t, J=7.0 Hz, 3H); MS (ESI) (m/z): 503 [M+H]⁺.

I-56:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide

MS (ESI) (m/z): 407 [M+H]⁺.

I-58:5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

MS (ESI) (m/z): 421 [M+H]⁺.

I-60:5-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamideformic acid salt

MS (ESI) (m/z): 411 [M+H]⁺.

I-62:N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H),8.09 (d, J=3.3 Hz, 1H), 7.82 (d, J=3.3 Hz, 1H), 7.29 (d, J=3.6 Hz, 1H),6.78 (d, J=3.6 Hz, 1H), 4.61 (tt, J=8.9, 7.3 Hz, 1H), 3.82 (qd, J=7.6,6.4 Hz, 1H), 3.40 (q, J=7.0 Hz, 2H), 2.80 (dddd, J=11.5, 7.1, 5.9, 2.6Hz, 2H), 2.46-2.31 (m, 2H), 1.14 (t, J=7.1 Hz, 3H) MS (ESI) (m/z): 425[M+H]⁺.

I-64:N-(1-(2-(2-methoxyethoxy)ethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.25 (s, 1H), 10.82 (s, 1H), 8.38 (s, 1H),8.26 (s, 1H), 8.09 (d, J=3.3 Hz, 1H), 7.98 (s, 1H), 7.80 (d, J=3.3 Hz,1H), 7.30 (dd, J=3.6, 0.5 Hz, 1H), 6.79 (d, J=3.5 Hz, 1H), 4.37 (t,J=5.2 Hz, 2H), 3.82 (t, J=5.2 Hz, 2H), 3.58-3.50 (m, 2H), 3.45-3.38 (m,2H), 3.21 (d, J=0.5 Hz, 3H); MS (ESI) (m/z): 429 [M+H]⁺.

I-65:5-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.40 (d, J=1.0 Hz, 1H), 8.09(dd, J=3.4, 1.0 Hz, 2H), 7.81 (dd, J=3.2, 1.2 Hz, 1H), 7.70-7.50 (m,3H), 7.30 (dd, J=3.6, 1.2 Hz, 1H), 6.79 (dd, J=3.6, 1.1 Hz, 1H), 4.56(tt, J=10.6, 6.0 Hz, 1H), 3.99 (dt, J=11.5, 3.3 Hz, 2H), 3.48 (td,J=11.2, 4.1 Hz, 2H), 2.09-1.95 (m, 4H); MS (ESI) (m/z): 411 [M+H]⁺.

I-67:N-{1-Methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (d, J=4.8 Hz, 1H), 8.34 (s, 1H), 8.25(bs, 1H), 8.01-7.9 (m, 3H), 7.43-7.38 (m, 1H), 7.26 (d, J=3.3 Hz, 1H),6.76 (d, J=3.3 Hz, 1H), 3.93 (s, 3H); MS (m/e) 335.16 MH⁺.

I-69:5-(1-Methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (d, J=4.8 Hz, 1H), 8.34 (s, 1H), 8.17(s, 1H), 8.00-7.9 (m, 3H), 7.43-7.39 (m, 1H), 7.26 (d, J=3.3 Hz, 1H),6.74 (d, J=3.6 Hz, 1H), 3.9 (s, 3H); MS (m/e) 349.12 MH⁺.

I-70:tert-Butyl-3-[4-{5-(1H-pyrazole-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate,formate salt

MS (m/e) 476.51 MH⁺

I-71:N-{1-(3-Methoxycyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(pyrazol-4-yl)furan-2-carboxamide,formate salt, Cis isomer

¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (d, J=4.2 Hz, 1H), 8.39 (s, 1H), 8.25(bs, 1H), 8.07-8.05 (m, 1H), 7.98-7.92 (m, 2H), 7.45-7.4 (m, 1H), 7.27(d, J=3.6 Hz, 1H), 6.77 (d, J=3.9 Hz, 1H), 4.64-4.58 (m, 1H), 3.78-3.73(m, 1H), 3.2 (s, 3H), 2.84-2.78 (m, 2H), 2.45-2.39 (m, 2H); MS (m/e)405.4 MH⁺.

I-72:N-{1-(3-Methoxycyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,Cis isomer

¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (d, J=4.2 Hz, 1H), 8.39 (s, 1H), 8.25(bs, 1H), 8.07-8.04 (m, 1H), 7.97-7.92 (m, 2H), 7.44-7.4 (m, 1H), 7.27(d, J=3.6 Hz, 1H), 6.77 (d, J=3.9 Hz, 1H), 4.64-4.58 (m, 1H), 3.78-3.73(m, 1H), 3.2 (s, 3H), 2.84-2.78 (m, 2H), 2.45-2.39 (m, 2H); MS (m/e)405.5 MH⁺.

I-73:N-{1-(3-Benzyloxy)cyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,Trans isomer

¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (d, J=5.7 Hz, 1H), 8.41 (s, 1H), 8.25(bs, 1H), 8.07-8.04 (m, 1H), 7.98-7.92 (m, 2H), 7.44-7.4 (m, 1H),7.37-7.36 (m, 4H), 7.33-7.28 (m, 1H), 7.26 (d, J=3.3 Hz, 1H), 6.76 (d,J=3.6 Hz, 1H), 5.15-5.1 (m, 1H), 4.45 (s, 2H), 4.43-4.38 (m, 1H),2.77-2.59 (m, 2H), 2.58-2.52 (m, 2H); MS (m/e) 481.53 MH⁺.

I-74:tert-Butyl-3-[4-{5-(1H-pyrazole-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate

¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (d, J=4.2 Hz, 1H), 8.45 (s, 1H), 8.24(m, 1H), 8.09-8.06 (m, 1H), 7.99-7.95 (m, 1H), 7.46-7.42 (m, 1H), 6.77(d, J=3.6 Hz, 1H), 5.34-5.32 (m, 1H), 4.32 (t, J=8.4 Hz, 2H), 4.2 (m,2H), 1.42 (s, 9H); MS (m/e) 476.78 MH⁺.

I-75:N-{1-(3-Methoxycyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,Trans isomer

¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (d, J=4.2 Hz, 1H), 8.4 (s, 1H), 8.25(bs, 1H), 8.07-8.05 (m, 1H), 7.98-7.92 (m, 2H), 7.44-7.4 (m, 1H), 7.27(d, J=3.6 Hz, 1H), 6.77 (d, J=3.9 Hz, 1H), 5.08-5.03 (m, 1H), 4.21-4.17(m, 1H), 3.2 (s, 3H), 2.73-2.64 (m, 2H); MS (m/e) 405.51 MH⁺.

I-77:N-{1-Methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,free base

¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (d, J=4.8 Hz, 1H), 8.34 (s, 1H), 8.25(bs, 1H), 8.01-7.9 (m, 3H), 7.43-7.38 (m, 1H), 7.26 (d, J=3.3 Hz, 1H),6.76 (d, J=3.3 Hz, 1H), 3.93 (s, 3H); MS (m/e) 335.16 MH⁺.

I-78:N-{1-(Azetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,TFA salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.78-8.76 (m, 1H), 8.58 (s, 1H), 8.15-7.99(m, 4H), 7.51-7.46 (m, 1H), 7.29 (d, J=3.3 Hz, 1H), 6.78 (d, J=3.3 Hz,1H), 5.56-5.51 (m, 1H), 4.46-4.39 (m, 4H); MS (m/e) 376.45 MH⁺.

I-80:Di-tert-butyl-[[4-{4-(5-((1-methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl}methyl]phosphate

¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (d, J=5.1 Hz, 1H), 8.37 (s, 1H), 8.35(s, 1H), 8.08 (bs, 1H), 8.01-7.9 (m, 2H), 7.39-7.35 (m, 1H), 7.29 (d,J=3.3 Hz, 1H), 6.87 (d, J=3.6 Hz, 1H), 5.97 (s, 1H), 5.93 (s, 1H), 3.93(s, 3H), 1.37 (s, 18H); MS (m/e) 557.69 MH⁺.

I-81:[4-{5-((1-Methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2yl}-1H-pyrazol-1-yl]methyldihydrogen phosphate

¹H NMR (300 MHz, DMSO-d₆) δ 8.82 (d, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.34(bs, 1H), 8.04 (s, 1H), 7.99-7.92 (m, 2H), 7.41-7.37 (m, 1H), 7.28 (d,J=3.6 Hz, 1H), 6.86 (d, J=3.6 Hz, 1H), 5.88 (d, J=10.8 Hz, 2H), 3.93 (s,3H); MS (m/e) 445.53 MH⁺.

I-82: Sodium[4-{5-((1-Methyl-3-(pyridine-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl}-1H-pyrazol-1-yl]methylphosphate

¹H NMR (300 MHz, D₂O) δ8.11 (bs, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.6(t, J=8.4 Hz, 1H), 7.49 (s, 1H), 7.37-7.34 (m, 1H), 7.07 (t, J=7.5 Hz,1H), 6.78 (d, J=3.9 Hz, 1H), 6.36 (d, J=3.6 Hz, 1H), 5.6 (d, J=6.6 Hz,2H), 3.6 (s, 3H); MS (m/e) 445.53 MH⁺.

I-83:N-{1-(1-Acetylazetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,free base

¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (d, J=4.2 Hz, 1H), 8.53 (s, 1H),8.1-8.08 (m, 1H), 7.99-7.94 (m, 1H), 7.47-7.43 (m, 1H), 7.28 (d, J=3.3Hz, 1H), 6.77 (d, J=3.6 Hz, 1H), 5.43-5.34 (m, 1H), 4.58 (t, J=8.7 Hz,1H), 4.5-4.46 (m, 1H), 4.31 (t, J=9.6 Hz, 1H), 4.2-4.16 (m, 1H), 1.84(s, 3H); MS (m/e) 418.61 MH⁺.

I-84:3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-(tert-butyl)azetidine-1-carboxamide,free base

¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (d, J=4.8 Hz, 1H), 8.47 (s, 1H),8.07-8.05 (m, 1H), 7.99-7.93 (m, 1H), 7.47-7.42 (m, 1H), 7.28 (d, J=3.3Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 5.87 (s, 1H), 5.3-5.25 (m, 1H), 4.24(t, J=8.4 Hz, 2H), 4.14-4.09 (m, 2H), 1.26 (s, 9H); MS (m/e) 475.65 MH⁺.

I-85:3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-isopropylazetidine-1-carboxamide,free base

¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (m, 1H), 8.47 (s, 1H), 8.25 (bs, 1H),8.08-8.05 (m, 1H), 7.99-7.96 (m, 2H), 7.47-7.42 (m, 1H), 7.29-7.28 (m,1H), 6.78-6.76 (m, 1H), 6.25 (d, J=8.1 Hz, 1H), 5.31 (m, 1H), 4.24 (t,J=8.4 Hz, 2H), 4.14-4.09 (m, 2H), 3.76-3.69 (m, 1H), 1.07 (s, 3H), 1.05(s, 3H); MS (m/e) 461.58 MH⁺.

I-86:3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-propylazetidine-1-carboxamide,free base

¹H NMR (300 MHz, DMSO-d₆) δ 8.75-8.74 (m, 1H), 8.47 (s, 1H), 8.25 (bs,1H), 8.08-8.05 (m, 1H), 7.99-7.93 (m, 2H), 7.47-7.42 (d, J=3.3 Hz, 1H),7.29-7.28 (d, J=3.6 Hz, 1H), 6.49 (m, 1H), 6.25 (d, J=8.1 Hz, 1H), 5.32(m, 1H), 4.25 (t, J=8.4 Hz, 2H), 4.16-4.12 (m, 2H), 3.0-2.94 (m, 2H),1.45-1.38 (m, 2H), 0.84 (t, J=7.5 Hz, 3H); MS (m/e) 461.58 MH⁺.

I-87:3-[4-{5-(1H-Pyrazol-4-yl)furan-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (bs, 1H), 8.47 (bs, 1H), 8.14-8.04 (bs,2H), 8.08-7.94 (m, 1H), 7.47-7.42 (m, 1H), 7.29-7.27 (m, 1H), 6.76 (m,1H), 5.31 (m, 1H), 4.24-4.21 (m, 2H), 4.18-4.12 (m, 2H), 0.55 (m, 2H),0.4 (m, 2H); MS (m/e) 459.57 MH⁺.

I-89:N-[1-{1-(Cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (d, J=5.1 Hz, 1H), 8.52 (s, 1H), 8.5(s, 1H), 8.1-8.08 (m, 1H), 7.99-7.94 (m, 1H), 7.47-7.43 (m, 1H), 7.28(d, J=3.3 Hz, 1H), 6.77 (d, J=3.9 Hz, 1H), 5.47-5.43 (m, 1H), 4.73 (t,J=8.4 Hz, 1H), 4.6 (m 1H), 4.37-4.3 (m, 1H), 4.2-4.16 (m, 1H), 1.66-1.59(m, 1H), 0.76 (s, 2H), 0.74 (s, 2H); MS (m/e) 444.61 MH⁺.

I-91:N-[1-{1-Pivaloylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (d, J=4.5 Hz, 1H), 8.51 (s, 1H),8.3-8.2 (ms, 1H), 8.08-8.05 (m, 1H), 7.99-7.94 (m, 2H), 7.47-7.43 (m,1H), 7.29-7.27 (m, 1H), 6.78-6.76 (m, 1H), 5.37 (m, 1H), 1.16 (s, 9H);MS (m/e) 460.61 MH⁺.

I-93:5-(1H-Pyrazol-4-yl)-N-{3-(pyridine-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.74 (m, 1H), 8.49 b (s, 1H), 8.25-8.2 (bs,1H), 8.06 (m, 1H), 7.96 (m, 2H), 7.44 (m, 1H), 7.28 (m, 1H), 6.77 (m,1H), 5.34 (m, 1H), 4.32-4.25 (m, 4H), 1.77 (bs, 4H); MS (m/e) 473.6 MH⁺.

I-95:N-[1-{1-Isobutyrylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formate salt

MS (m/e) 446.55 MH⁺.

I-97:N-(1H-Pyrazol-4-yl)-N-{3-(pyridine-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide,TFA salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.74 (d, J=4.5 Hz, 1H), 8.54 (s, 1H),8.09-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.46-7.42 (m, 1H), 7.28 (d, J=3.6Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 5.21-5.16 (m, 1H), 3.89 (t, J=7.8 Hz,2H), 3.74 (t, J=7.2 Hz, 2H), 3.38 (q, J=9.9 Hz, 2H); MS (m/e) 458.55MH⁺.

I-75:N-[1-{1-Butyrylazetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.75-8.74 (m, 1H), 8.52 (s, 1H), 8.09-8.06(m, 1H), 7.99-7.94 (m, 2H), 7.47-7.43 (m, 1H), 7.29-7.27 (m, 1H),6.78-6.77 (m, 1H), 5.39 (m, 1H), 4.59 (t, J=8.7 Hz, 1H), 4.5-4.45 (m,1H), 4.32 (t, J=9.9 Hz, 1H), 4.2-4.16 (m, 1H), 2.1 (t, J=7.5 Hz, 2H),1.53 (q, J=7.5 Hz, 2H), 0.9 (t, J=7.2 Hz, 9H); MS (m/e) 446.58 MH⁺.

I-101:N-{1-(1-Methylazetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (d, J=5.7 Hz, 1H), 8.07 (s, 1H), 7.8(s, 1H), 7.63-7.61 (m, 1H), 7.55-7.49 (m, 1H), 7.01-6.97 (m, 1H), 6.83(d, J=3.6 Hz, 1H), 6.33 (d, J=3.6 Hz, 1H), 4.64-4.59 (m, 1H), 3.26 (t,J=8.1 Hz, 2H), m (t, 2H); MS (m/e) 390.55 MH⁺.

I-103:N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridine-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide,formate salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.76 (m, 1H), 8.55 (s, 1H), 8.53 (s, 1H),8.25 (m, 1H), 8.11-8.08 (m, 1H), 7.99-7.94 (m, 2H), 7.47-7.43 (m, 1H),7.29 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 5.46 (m, 1H), 4.8 (m,1H), 4.69 (m, 1H), 4.57 (m, 1H), 4.4 (m, 1H), 4.3 (m, 1H), 2.79 (m, 1H),1.9 (m, 2H); MS (m/e) 480.49 MH⁺.

I-105:N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.38 (d, J=2.9 Hz, 1H), 8.28(s, 1H), 8.10 (s, 2H), 7.85 (d, J=8.9 Hz, 1H), 7.56 (dd, J=8.9, 2.9 Hz,1H), 7.25 (d, J=3.6 Hz, 1H), 6.74 (d, J=3.6 Hz, 1H), 3.91 (s, 3H), 3.80(t, J=4.9 Hz, 4H), 3.27 (t, J=4.9 Hz, 4H).

LCMS (m/z): 420.55 (MH⁺).

I-106:N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.31 (s, 1H), 11.69 (s, 1H), 8.37 (d, J=2.9Hz, 1H), 8.27 (m, 8.27-8.23, 2H), 7.98 (s, 1H), 7.83 (d, J=8.9 Hz, 1H),7.55 (dd, J=8.9, 2.9 Hz, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.6 Hz,1H), 3.90 (s, 3H), 3.32 (t, J=6.4 Hz, 4H), 2.51 (t, J=6.4 Hz, 4H), 2.26(s, 3H).

LCMS (m/z): 433.72 (MH⁺).

I-107:N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-arboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.30 (s, 1H), 11.46 (s, 1H), 8.43 (s, 1H),8.32 (s, 1H), 8.27 (s, 1H), 8.01-7.91 (m, 2H), 7.60 (dd, J=8.9, 2.9 Hz,1H), 7.28 (d, J=3.6 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 4.72 (s, 1H), 3.92(s, 3H), 3.90 (s, 3H), 1.25 (s, 6H).

LCMS (m/z): 423.60 (MH⁺).

I-108:N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.34 (s, 1H), 11.45 (s, 1H), 8.32 (s, 1H),8.25 (d, J=2.6 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.45 (dd, J=8.9, 2.9 Hz,1H), 7.28 (d, J=3.6 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 6.62 (s, 1H), 5.48(p, J=5.4, 5.0 Hz, 1H), 5.00 (t, J=6.9 Hz, 2H), 4.70-4.63 (m, 2H), 3.92(s, 3H).

LCMS (m/z): 407.35 (MH⁺).

I-109:N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.33 (s, 1H), 11.55 (s, 1H), 8.44 (d, J=2.9Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.00-7.97 (m, 2H), 7.62 (dd, J=8.9,3.0 Hz, 1H), 7.31 (d, J=3.5 Hz, 1H), 6.81 (d, J=3.5 Hz, 1H), 3.96 (s,3H), 3.96 (s, 3H); LRMS (M+H) m/z 365.57.

I-110:N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.31 (s, 1H), 11.70 (s, 1H), 8.78 (ddd,J=5.0, 1.6, 1.0 Hz, 1H), 8.42 (s, 1H), 8.31-8.30 (m, 1H), 8.08 (ddd,J=8.1, 1.1, 1.1 Hz, 1H), 8.02-7.96 (m, 2H), 7.46 (ddd, J=7.3, 5.0, 1.3Hz, 1H), 7.31 (d, J=3.5 Hz, 1H), 6.82 (d, J=3.5 Hz, 1H), 4.67 (hept,J=6.7 Hz, 1H), 1.53 (d, J=6.7 Hz, 6H); LRMS (M+H) m/z 363.67.

I-111:N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, Chloroform-d) δ 11.82 (s, 1H), 10.31 (v br s, 1H), 8.67(ddd, J=5.0, 1.7, 1.0 Hz, 1H), 8.41 (s, 1H), 8.09 (ddd, J=8.1, 1.1, 1.1Hz, 1H), 7.99 (s, 2H), 7.78 (ddd, J=8.0, 7.6, 1.8 Hz, 1H), 7.26-7.21 (m,2H, partially overlapped with CHCl₃), 6.53 (d, J=3.5 Hz, 1H), 4.30 (t,J=6.7 Hz, 2H), 3.73-3.70 (m, 4H), 2.90 (t, J=6.7 Hz, 2H), 2.54-2.51 (m,4H); LRMS (M+H) m/z 434.84.

I-112:N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.33 (br s, 1H), 11.69 (s, 1H), 8.77 (ddd,J=5.0, 1.6, 1.0 Hz, 1H), 8.46 (s, 1H), 8.15 (br s, 2H), 8.06 (ddd,J=8.1, 1.2 Hz, 1H), 7.98 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.46 (ddd,J=7.3, 5.0, 1.4 Hz, 1H), 7.32 (d, J=3.6 Hz, 1H), 6.82 (d, J=3.6 Hz, 1H),4.35 (t, J=6.5 Hz, 2H), 3.41 (br s, 2H), 2.80 (t, J=6.5 Hz, 3H), 2.50(br s, partially overlapped with DMSO, 2H), 2.34 (br s, 4H), 2.17 (s,3H); LRMS (M+H) m/z 447.76.

I-113:5-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)furan-2-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.74 (d, J=6.7 Hz, 1H), 8.42(s, 1H), 8.27 (s, 1H), 8.05-7.93 (m, 3H), 7.46-7.42 (m, 1H), 7.28 (d,J=3.3 Hz, 1H), 6.79 (d, J=3.3 Hz, 1H), 4.43 (t, J=6.7 Hz, 2H), 4.16-4.01(m, 4H); LCMS (m/z): 447.13 (MH⁺).

I-114:N-(1-((1,3-cis)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.73 (d, J=4.8 Hz, 1H), 8.38(s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.97 (t, J=7.8 Hz, 1H), 7.42 (t, d=6.3Hz, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.6 Hz, 1H), 4.58 (m, 1H),3.89 (p, J=6.6 Hz, 1H), 3.62 (p, J=6.3 Hz, 1H), 2.78 (m, 2H), 2.41 (m,2H), 1.10 (d, J=6.3 Hz, 6H); LCMS: purity: 91.77%; MS (m/e): 433.22(MH+).

I-115:N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 11.69 (s, 1H), 8.81 (d, J=7.5Hz, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.03 (t,J=8.1 Hz, 1H), 7.96 (s, 1H), 7.92 (t, J=58.5 Hz, 1H), 7.55 (dd, J=7.4,5.0 Hz, 1H), 7.34 (d, J=3.6 Hz, 1H), 6.79 (d, J=3.6 Hz, 1H); LCMS:purity: 100%; MS (m/e): 371.18 (MH+).

I-116:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.22 (s, 1H), 10.43 (s, 1H), 8.50 (s, 1H),8.33 (d, J=8.1 Hz, 1H), 8.20 (t, J=8.1 Hz, 1H), 8.15 (s, 1H), 7.88 (d,J=8.4 Hz, 2H), 7.25 (d, J=3.6 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 4.64 (p,J=7.9 Hz, 1H), 3.84 (p, J=6.9 Hz, 1H), 3.41 (q, J=6.9 Hz, 2H), 2.85-2.77(m, 2H), 2.44-2.37 (m, 2H), 1.13 (t, J=7.0 Hz, 3H); LCMS: purity: 100%;MS (m/e): 487.25 (MH+).

I-117:5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)furan-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.26 (s, 1H), 11.67 (s, 1H), 8.76 (d, J=5.1Hz, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 8.05-7.95 (m, 3H), 7.47 (t, J=5.1Hz, 1H), 7.29 (d, J=3.6 Hz, 1H), 6.78 (d, J=3.3 Hz, 1H), 5.28 (q, J=9.1Hz, 2H); LCMS: purity: 100%; MS (m/e): 403.18 (MH+); LCMS: purity: 100%;MS (m/e): 403.18 (MH+).

I-119:N-(1-(2-ethoxyethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.11 (s, 2H), 8.07 (d, J=3.3Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.28 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.5Hz, 1H), 4.34 (t, J=5.3 Hz, 2H), 3.81-3.71 (m, 2H), 3.43 (q, J=7.0 Hz,2H), 1.06 (t, J=7.0 Hz, 3H).

MS (ESI) (m/z): 399 [M+H]⁺

I-120:5-(1H-pyrazol-4-yl)-N-(1-(tetrahydrofuran-3-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.20 (s, 1H), 10.78 (s, 1H), 8.32 (s, 1H),8.20 (s, 1H), 8.03 (d, J=3.3 Hz, 1H), 7.91 (s, 1H), 7.76 (d, J=3.3 Hz,1H), 7.24 (d, J=3.6 Hz, 1H), 6.73 (d, J=3.6 Hz, 1H), 5.11 (dq, J=8.5,4.1 Hz, 1H), 4.03-3.88 (m, 3H), 3.76 (td, J=8.3, 5.8 Hz, 1H), 2.42-2.31(m, 1H), 2.30-2.17 (m, 1H).

MS (ESI) (m/z): 397 [M+H]⁺

I-122:5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide

MS (ESI) (m/z): 429 [M+H]⁺

I-124:N-(1-((cis)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.23 (s, 1H), 11.64 (s, 1H), 8.72 (d, J=3.0Hz, 1H), 8.34 (s, 1H), 7.98 (m, 3H), 7.39 (m, 1H), 7.26 (d, J=3.6 Hz,1H), 6.77 (d, J=3.6 Hz, 1H), 6.49 (s, 1H), 4.58 (m, 1H), 4.27 (m, 1H),3.85 (m, 1H), 2.21 (m, 2H), 1.88 (m, 4H), 1.58 (m, 2H).

LCMS: purity: 81.36%. MS (m/e): 418.46 (MH⁺).

I-126:N-(1-((trans)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 11.64 (s, 1H), 8.71 (d, J=5.1Hz, 1H), 8.35 (s, 1H), 8.24 (m, 1H), 7.95 (m, 3H), 7.40 (t, J=6.9 Hz,1H), 7.25 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.6 Hz, 1H), 4.66 (m, 1H), 4.25(m, 1H), 4.27 (m, 1H), 3.52 (m, 1H), 1.95 (m, 6H), 1.38 (m, 2H). LCMS:purity: 89.15%. MS (m/e): 418.46 (MH+).

I-128:5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((trans)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.25 (s, 1H), 11.64 (s, 1H), 8.73 (d, J=4.8Hz, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.96 (t,J=7.8 Hz, 1H), 7.43 (t, J=6.0 Hz, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.77 (d,J=3.6 Hz, 1H), 5.08 (m, 1H), 4.54 (m, 1H), 4.06 (m, 2H), 2.74 (m, 2H),2.58 (m, 2H). LCMS: purity: 92.43%. MS (m/e): 472.43 (MH⁺).

I-130:N-(1-((trans)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.20 (s, 1H), 11.59 (s, 1H), 8.67 (d, J=4.2Hz, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 7.92 (m, 2H), 7.35 (m, 2H), 7.21(d, J=3.3 Hz, 1H), 4.77 (m, 1H), 3.93 (m, 1H), 3.40 (m, 2H), 2.04 (m,4H), 1.81 (m, 2H), 1.73 (t, J=6.9 Hz, 3H). LCMS: purity: 93.93%. MS(m/e): 446.51 (MH⁺).

I-132:N-(1-((cis)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.20 (s, 1H), 11.59 (s, 1H), 8.67 (d, J=4.8Hz, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 7.92 (m, 2H), 7.35 (m, 1H), 7.21(d, J=3.3 Hz, 1H), 6.71 (d, J=3.6 Hz, 1H), 4.24 (m, 1H), 3.44 (m, 2H),2.01 (m, 4H), 1.81 (m, 2H), 1.32 (m, 2H), 1.05 (t, J=6.9 Hz, 3H). LCMS:purity: 98.04%. MS (m/e): 432.48 (MH⁺).

I-134:N-(1-((cis)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.43(d, J=14.7 Hz, 1H), 8.10 (s, 1H), 7.94 (m, 2H), 7.41 (m, 1H), 7.27 (m,1H), 6.77 (d, J=3.6 Hz, 1H), 4.79 (m, 1H), 4.20 (m, 1H), 2.39 (m, 2H),2.06 (m, 2H), 1.80 (m, 2H). LCMS: purity: 93.14%.

MS (m/e): 404.43 (MH⁺).

I-136:N-(1-((trans)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.63 (s, 1H), 8.71 (d, J=3.9 Hz, 1H), 8.43(d, J=6.3 Hz, 1H), 8.37 (s, 1H), 8.09 (m, 1H), 7.93 (m, 3H), 7.40 (m,1H), 7.27 (m, 1H), 7.76 (d, J=3.6 Hz, 1H), 4.97 (m, 1H), 4.37 (m, 1H),2.33 (m, 2H), 2.07 (m, 2H), 1.93 (m, 2H). LCMS: purity: 90.43%. MS(m/e): 404.43 (MH⁺).

I-138:N-(1-((cis)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.24 (s, 1H), 11.20 (s, 1HO, 8.71 (d, J=3.0Hz, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 8.12 (m, 1H), 7.88 (m, 2H), 7.27(m, 1H), 6.76 (m, 1H), 4.60 (m, 1H), 3.82 (m, 1H), 3.36 (m, 2H), 2.77(m, 2H), 2.42 (m, 2H), 1.21 (t, J=7.2 Hz, 3H). LCMS: purity: 100%. MS(m/e): 436.45 (MH⁺).

I-140:N-(1-((cis)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, CDCl₃) δ 11.81 (s, 1H), 8.66 (d, J=3.3 Hz, 1H), 8.42(s, 1H), 8.14 (m, 1H), 7.79 (m, 1H), 7.48 (m, 2H), 7.25 (m, 2H), 6.53(m, 1H), 5.29 (m, 1H), 4.42 (m, 1H), 3.97 (m, 1H), 3.64 (m, 1H), 2.75(m, 1H), 2.17 (m, 1H), 1.59 (m, 1H), 1.29 (t, J=7.5 Hz, 3H).

LCMS: purity: 94.28%. MS (m/e): 436.45 (MH⁺).

I-142:N-(1-((cis)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.25 (s, 1H), 11.44 (s, 1H), 8.62 (m, 1H),8.45 (s, 1H), 8.09 (s, 2H), 7.91 (m, 1H), 7.54 (m, 1H), 7.27 (m, 1H),6.76 (d, J=3.6 Hz, 1H), 4.62 (m, 1H), 3.81 (m, 1H), 3.39 (m, 2H), 2.79(m, 2H), 2.41 (m, 2H), 1.13 (t, J=7.2 Hz, 3H). LCMS: purity: 100%. MS(m/e): 436.45 (MH⁺).

I-144:N-(1-((cis)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.28 (s, 1H), 10.90 (s, 1H), 8.44 (s, 1H),8.23 (s, 1H), 8.12 (m, 1H), 7.98 (m, 1H), 7.50 (m, 2H), 7.27 (m, 1H),6.78 (d, J=3.6 Hz, 1H), 4.62 (m, 1H), 3.83 (m, 1H), 3.37 (m, 2H), 2.80(m, 2H), 2.48 (m, 2H, 1.15 (t, J=6.9 Hz, 3H). LCMS: purity: 100%. MS(m/e): 436.45 (MH⁺).

I-146:5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((cis)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.63 (s, 1H), 8.74 (t, J=4.8 Hz, 1H), 8.42(s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.93 (m, 2H), 7.42 (m, 1H), 7.26(d, J=3.9 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 5.08 (m, 1H), 4.54 (m, 1H),4.06 (m, 2H), 2.75 (m, 2H), 2.54 (m, 2H). LCMS: purity: 95.52%. MS(m/e): 472.43 (MH⁺).

I-148:N-(1-((cis)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 12.02 (s, 1H), 8.81 (m, 1H),8.50 (m, 2H), 8.29 (s, 1H), 7.80 (s, 1H), 7.76 (m, 1H), 7.34 (m, 2H),4.56 (m, 1H), 3.84 (m, 1H), 3.43 (m, 2H), 2.80 (m, 2H), 2.42 (m, 2H),1.16 (t, J=6.9 Hz, 3H). LCMS: purity: 100%. MS (m/e): 436.45 (MH⁺).

I-150:N-(3-(6-fluoropyridin-2-yl)-1-((cis)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.24 (s, 1H), 11.45 (s, 1H), 8.62 (d, J=4.5Hz, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 7.91 (m, 2H), 7.52 (m, 1H), 7.27(d, J=3.3 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 5.10 (m, 1H), 4.51 (m, 1H),4.03 (m, 2H), 2.72 (m, 2H), 2.54 (m, 2H). LCMS: purity: 97.7%. MS (m/e):490.42 (MH⁺).

I-152:N-(3-(3-fluoropyridin-2-yl)-1-((cis)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.24 (s, 1H), 11.44 (s, 1H), 8.62 (d, J=4.5Hz, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.91 (m, 2H), 7.54 (m, 1H), 7.27(d, J=3.3 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 4.64 (m, 1H), 4.06 (m, 2H),3.58 (m, 1H), 2.83 (m, 2H), 2.54 (m, 2H). LCMS: purity: 94.59%. MS(m/e): 490.42 (MH⁺).

I-154:N-(1-((trans)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 11.47 (s, 1H), 8.62 (d, J=4.2Hz, 1H), 8.50 (s, 2H), 8.41 (s, 1H), 7.90 (m, 2H), 7.50 (m, 1H), 7.26(d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 4.31 (m, 1H), 3.46 (m, 2H),3.36 (m, 1H), 2.05 (m, 4H), 1.82 (m, 2H), 1.35 (m, 2H), 1.12 (t, J=7.2Hz, 3H). LCMS: purity: 100%. MS (m/e): 464.50 (MH⁺).

I-156:N-(3-(3,6-difluoropyridin-2-yl)-1-((cis)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 10.75 (s, 1H), 8.48 (s, 1H),8.21 (s, 1H), 8.13 (m, 1H), 7.98 (s, 1H), 7.29 (m, 2H), 6.78 (d, J=3.6Hz, 1H), 4.63 (m, 1H), 3.83 (m, 1H), 3.42 (m, 2H), 2.78 (m, 2H), 2.41(m, 2H), 1.13 (t, J=7.2 Hz, 3H). LCMS: purity: 100%.

MS (m/e): 454.44 (MH⁺).

II-2: 1-(isobutyryloxy)ethyl4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate

¹H NMR (DMSO d₆, 300 MHz): δ 12.23 (s, 1H), 9.12 (s, 1H), 8.75-8.73 (m,IH), 8.48-8.43 (m, 3H), 8.02-7.91 (m, 2H), 7.42-7.38 (m, 1H), 7.05-7.00(m, IH), 3.96 (s, 3H), 2.63 (septet, J=6.7 Hz, IH), 1.66 (d, J=6.7 Hz,3H), 1.14-1.11 (m, 6H); LCMS (m/z): 422.60 (MH⁺).

II-3: tert-butyl(S)-(3-methyl-1-(4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-1-oxobutan-2-yl)carbamate

¹H NMR (DMSO d₆, 300 MHz): δ 12.22 (s, 1H), 9.21 (s, 1H), 8.79-8.76 (m,IH), 8.51-8.44 (m, 3H), 8.02-7.91 (m, 2H), 7.53-7.40 (m, 2H), 5.26-5.24(m, IH), 3.96 (s, 3H), 1.40 (s, 9H), 1.23-1.18 (m, 1H), 0.95 (d, J=6.7Hz, 6H), 0.86-0.80 (m, 1H); LCMS (m/z): 551.72 (MH⁺).

II-4:2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.95 (s, 1H), 8.77 (d, J=6.2Hz, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.05-7.87 (m, 2H),7.42 (t, J=6.6 Hz, 1H), 3.96 (s, 3H), 2.45 (s, 3H); LCMS (m/z): 464.61(MH⁺).

II-5: 1-methylcyclopropyl4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate

¹H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.02 (t, J=0.6 Hz, 1H), 8.73(ddd, J=5.0, 1.7, 0.9 Hz, 1H), 8.58-8.27 (m, 3H), 8.15-7.77 (m, 3H),7.41 (ddd, J=7.1, 4.9, 1.5 Hz, 1H), 3.96 (d, J=0.6 Hz, 3H), 1.69 (s,3H), 1.33-1.04 (m, 2H), 1.03-0.70 (m, 2H); LCMS (m/z): 450.60 (MH⁺).

II-6: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate

¹H NMR (300 MHz, DMSO-d6) δ 12.34-12.12 (m, 1H), 9.07-8.85 (m, 1H),8.83-8.61 (m, 1H), 8.54-8.34 (m, 2H), 7.96 (dtd, J=16.9, 8.0, 1.4 Hz,2H), 7.38 (ddd, J=7.3, 4.8, 1.3 Hz, 1H), 7.34-7.11 (m, 2H), 6.94-6.70(m, 2H), 4.49 (s, 2H), 3.96 (d, J=1.1 Hz, 3H), 3.81-3.60 (m, 5H),1.80-1.47 (m, 6H); LCMS (m/z): 588.74 (MH⁺).

II-7: diethyl((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate

LCMS (m/z): 502.52 (MH⁺).

II-8: sodium((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate

¹H NMR (300 MHz, Deuterium Oxide) δ 8.14 (t, J=6.0 Hz, 2H), 7.94-7.69(m, 1H), 7.71-7.45 (m, 3H), 7.31 (t, J=9.7 Hz, 1H), 7.25-7.01 (m, 1H),4.29 (d, J=13.3 Hz, 2H), 3.67 (s, 3H); LCMS (m/z): 446.50 (MH⁺).

II-10:2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 12.21 (s, 1H), 8.96-8.67 (m,1H), 8.48 (d, J=2.8 Hz, 2H), 8.42-8.22 (m, 1H), 8.25-7.80 (m, 3H),7.59-7.19 (m, 1H), 4.56 (s, 1H), 4.00 (dd, J=10.8, 3.7 Hz, 2H),3.73-3.39 (m, 2H), 2.19-1.82 (m, 4H); LCMS (m/z): 422.52 (MH⁺).

II-12:N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.18 (s, 1H), 8.75 (d, J=4.2Hz, 1H), 8.47 (m, 2H), 8.27 (s, 1H), 8.09 (s, 1H), 8.04 (d, J=8.1 Hz,1H), 7.93 (t, J=7.2 Hz, 1H), 7.42 (dd, J=5.1 Hz, 1H), 5.06 (p, J=6.9 Hz,1H), 4.28 (p, J=6.6 Hz, 1H), 3.40 (q, J=6.9 Hz, 2H), 2.71 (m, 2H), 1.14(t, J=6.9 Hz, 3H); LCMS: purity: 86.42%; MS (m/e): 436.50 (MH+).

II-13:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.77 (d, J=4.5 Hz, 1H), 8.46(s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.04 (m, 2H), 7.93 (t, J=8.7 Hz,1H), 7.42 (dd, J=6.0 Hz, 1H), 4.61 (p, J=7.5 Hz, 1H), 3.95 (s, 3H), 3.83(p, J=6.6 Hz, 1H), 3.41 (q, J=6.9 Hz, 2H), 2.80 (m, 2H), 2.41 (m, 2H),1.14 (t, J=6.9 Hz, 3H); LCMS: purity: 96.61%; MS (m/e): 450.77 (MH+).

II-14:N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.19 (s, 1H), 8.75 (d, J=4.5Hz, 1H), 8.48 (s, 2H), 8.28 (s, 1H), 8.10 (s, 1H), 8.03 (d, J=7.8 Hz,1H), 7.93 (t, J=8.4 Hz, 1H), 7.41 (ddd, J=7.4, 4.9, 1.3 Hz, 1H), 5.32(d, J=6.6 Hz, 1H), 4.48 (p, J=6.6 Hz, 1H), 3.96 (q, J=6.6 Hz, 1H),2.82-2.74 (m, 2H), 2.41-2.34 (m, 2H); LCMS: purity: 97.58%; MS (m/e):408.53 (MH+).

II-15:N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.40 (br, 1H), 12.19 (s, 1H), 8.76 (d,J=4.5 Hz, 1H), 8.52 (d, J=8.7 Hz, 2H), 8.28 (s, 1H), 8.12 (s, 1H), 8.04(d, J=7.8 Hz, 1H), 7.94 (td, J=7.8, 1.8 Hz, 1H), 7.42 (dd, J=6.6 Hz,1H), 4.73 (p, J=8.1 Hz, 1H), 2.71 (m, 2H), 2.40 (s, 6H); LCMS: purity:100%; MS (m/e): 435.57 (MH+).

II-16:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate bis-sodium salt

1H NMR (300 MHz, Deuterium Oxide) δ 7.77 (s, 1H), 7.67 (s, 1H), 7.50 (s,1H), 7.45 (s, 1H), 7.31 (s, 1H), 7.08 (m, 2H), 6.95 (s, 1H), 5.50 (d,J=9.3 Hz, 2H), 4.10 (t, J=7.5 Hz, 1H), 3.87 (t, J=7.5 Hz, 1H), 3.46 (q,J=6.9 Hz, 2H), 2.78 (m, 2H), 2.14 (m, 2H), 1.12 (t, J=6.9 Hz, 3H); LCMS:purity: 100%; MS (m/e): 546.57 (MH+).

II-18:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 12.20 (s, 1H), 8.76 (ddd, J=4.9, 1.7, 1.0Hz, 1H), 8.46 (s, 1H), 8.29 (d, J=0.5 Hz, 1H), 8.06-7.87 (m, 2H), 7.42(ddd, J=7.3, 4.9, 1.4 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 3.80 (t, J=5.3Hz, 2H), 3.50-3.42 (m, 2H), 1.17-1.00 (m, 3H); MS (ESI) (m/z): 410[M+H]⁺.

II-19:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.70 (d, J=1.1 Hz, 1H), 8.60(dt, J=5.0, 1.4 Hz, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.00 (dt, J=8.1,1.2 Hz, 1H), 7.90 (td, J=7.7, 1.8 Hz, 1H), 7.36 (ddd, J=7.4, 5.0, 1.3Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 3.79 (t, J=5.3 Hz, 2H), 3.46 (dd,J=14.0, 7.0 Hz, 2H), 1.09 (t, J=7.0 Hz, 3H); MS (ESI) (m/z): 478 [M+H]⁺.

II-21:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (ddd, J=5.0, 1.7, 0.9 Hz, 1H), 8.51 (s,1H), 8.31 (d, J=0.6 Hz, 1H), 8.05-7.98 (m, 1H), 7.92 (td, J=7.7, 1.8 Hz,1H), 7.67-7.50 (m, 3H), 7.44-7.35 (m, 1H), 4.36 (t, J=5.3 Hz, 2H),3.84-3.75 (m, 2H), 3.46 (q, J=6.9 Hz, 2H), 2.70 (s, 3H), 1.15-1.02 (m,3H); MS (ESI) (m/z): 424 [M+H]⁺.

II-23:2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 11.64 (s, 1H), 8.58 (dd, J=3.9, 2.7 Hz, 1H),8.53 (s, 1H), 8.35 (d, J=0.3 Hz, 1H), 8.07-7.97 (m, 1H), 7.91 (td,J=7.7, 1.8 Hz, 1H), 7.38 (ddd, J=7.5, 5.0, 1.3 Hz, 1H), 4.36 (t, J=5.3Hz, 2H), 3.84-3.74 (m, 2H), 3.50-3.41 (m, 2H), 2.63 (s, 3H), 2.57 (s,3H), 1.09 (t, J=7.0 Hz, 3H); MS (ESI) (m/z): 438 [M+H]⁺.

II-26:N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 12.20 (s, 1H), 8.76 (d, J=4.8 Hz, 0H),8.59-8.45 (s br, 1H), 8.43 (s, 1H), 8.30 (d, J=0.4 Hz, 1H), 8.13 (s br,1H), 8.02-7.89 (m, 2H), 7.41 (ddd, J=7.2, 4.9, 1.5 Hz, 1H), 3.96 (s,3H); MS (ESI) (m/z): 352 [M+H]⁺.

II-27:2-(3-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.62 (ddd, J=5.1, 1.7, 0.9Hz, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.05-7.95 (m, 1H), 7.89 (td, J=7.8,1.8 Hz, 1H), 7.83-7.65 (m, 1H), 7.36 (ddd, J=7.4, 5.0, 1.3 Hz, 1H), 3.94(s, 3H), 2.68 (s, 3H); MS (ESI) (m/z): 366 [M+H]⁺.

II-28:N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 12.21 (s, 1H), 8.82-8.73 (m, 1H), 8.46 (d,J=0.8 Hz, 1H), 8.36-8.27 (m, 3H), 8.06-7.87 (m, 2H), 7.46-7.37 (m, 1H),4.38 (t, J=5.4 Hz, 2H), 3.81-3.72 (m, 2H), 3.27 (s, 3H); MS (ESI) (m/z):395 [M+H]⁺.

II-29:N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamideformic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 11.85 (s, 1H), 8.67-8.61 (m, 1H), 8.49 (s,1H), 8.30 (s, 1H), 8.15 (s, 1H), 8.05-7.99 (m, 1H), 7.92 (td, J=7.7, 1.8Hz, 1H), 7.39 (ddd, J=7.4, 5.0, 1.3 Hz, 1H), 4.38 (t, J=5.2 Hz, 2H),3.76 (t, J=5.2 Hz, 2H), 3.27 (s, 3H), 2.69 (s, 3H); MS (ESI) (m/z): 410[M+H]⁺.

II-31:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 424 [M+H]⁺.

II-32:2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamideformic acid salt

MS (ESI) (m/z): 338 [M+H]⁺.

II-34:N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.43 (s, 1H), 12.22 (s, 1H), 8.78 (ddd,J=5.0, 1.8, 0.9 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J=3.5 Hz, 0H), 8.29 (s,1H), 8.10 (dt, J=8.0, 1.1 Hz, 1H), 7.96 (td, J=7.8, 1.8 Hz, 1H), 7.45(ddd, J=7.5, 4.9, 1.3 Hz, 1H), 5.72 (tt, J=7.4, 6.5 Hz, 1H), 4.98 (dd,J=6.9, 2.0 Hz, 4H); MS (ESI) (m/z): 394 [M+H]⁺.

II-36: Sodium(4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate

¹H NMR (300 MHz, DMSO-d₆) δ 12.21 (s, 1H), 8.86 (dt, J=4.8, 1.3 Hz, 1H),4.68-4.35 (m, 2H), 8.63 (d, J=0.8 Hz, 1H), 8.38 (s, 1H), 8.23 (s, 1H),8.02 (d, J=0.8 Hz, 1H), 7.96-7.81 (m, 2H), 7.42 (ddd, J=6.9, 4.9, 1.5Hz, 1H), 5.72 (d, J=10.9 Hz, 2H), 3.94 (s, 3H); MS (ESI) (m/z): 462[M+H]⁺.

II-37:N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, Acetone-d₆) δ 11.75 (d, J=2.6 Hz, 1H), 8.31 (dt, J=3.0,1.4 Hz, 1H), 8.09-7.94 (m, 1H), 7.95-7.78 (m, 2H), 7.63-7.41 (m, 2H),6.96 (dddd, J=7.4, 4.9, 2.3, 1.2 Hz, 1H), 3.98-3.85 (m, 2H), 3.45-3.34(m, 2H), 3.16-3.05 (m, 2H), 2.97 (dt, J=3.0, 1.8 Hz, 2H), 2.76 (s, 3H);MS (ESI) (m/z): 440 [M+H]⁺.

II-38: Potassium(4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate

MS (ESI) (m/z): 462 [M+H]⁺.

II-39:N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 454 [M+H]⁺.

II-41:2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide,formic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.67 (ddd, J=5.0, 1.8, 1.0Hz, 1H), 8.62 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.17-8.09 (m, 1H),7.96 (td, J=7.8, 1.8 Hz, 1H), 7.44 (ddd, J=7.6, 5.0, 1.3 Hz, 1H),5.80-5.66 (m, 1H), 4.98 (dd, J=6.9, 1.7 Hz, 4H), 2.69 (s, 3H); MS (ESI)(m/z): 408 [M+H]⁺.

II-43:2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamideformic acid salt

MS (ESI) (m/z): 408 [M+H]⁺.

II-45:2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamideformic acid salt

MS (ESI) (m/z): 436 [M+H]⁺.

II-47:N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamideformic acid salt

MS (ESI) (m/z): 438 [M+H]⁺.

II-49:N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamideformic acid salt

¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.76 (dt, J=4.9, 1.4 Hz, 1H),8.48 (s, 1H), 8.37-8.30 (m, 2H), 8.29 (s, 1H), 8.04-7.98 (m, 1H), 7.93(td, J=7.7, 1.8 Hz, 1H), 7.41 (ddd, J=7.3, 4.9, 1.4 Hz, 1H), 4.25 (t,J=6.4 Hz, 2H), 3.60-3.44 (m, 4H), 2.85 (t, J=6.4 Hz, 2H), 0.93 (t, J=7.1Hz, 6H); MS (ESI) (m/z): 437 [M+H]⁺.

II-54:tert-Butyl-3-[4-{2-(1H-pyrazole-4-yl)thiazole-2-carboxamido}-3-(pyridine-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate,free base

¹H NMR (300 MHz, DMSO-d₆) δ 8.76 (d, J=5.1 Hz, 1H), 8.55 (s, 1H), 8.5(bs, 1H), 8.29 (s, 1H), 8.11-8.05 (m, 2H), 7.98-7.92 (m, 1H), 7.46-7.42(m, 1H), 5.38-5.33 (m, 1H), 4.33 (t, J=8.7 Hz, 2H), 4.23-3.36 (m, 2H),1.42 (s, 9H); MS (m/e) 493.62 MH⁺.

II-55:N-{1-(Azetidin-3-yl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide,TFA salt

¹H NMR (300 MHz, DMSO-d₆) δ 8.8 (d, J=5.1 Hz, 1H), 8.66 (s, 1H), 8.3 (s,2H), 8.13-8.1 (m, 1H), 8.03-7.98 (m, 1H), 7.5-7.46 (m, 1H), 5.57-5.52(m, 1H), 4.45-4.41 (m, 4H); MS (m/e) 393.54 MH⁺.

II-57:N-{1-(3-Methoxycyclobutyl)-3-(pyridine-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide,free base, Cis isomer

¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (d, J=4.8 Hz, 1H), 8.49 (bs, 1H), 8.46(s, 1H), 8.26 (bs, 1H), 8.1 (bs, 1H), 8.05-8.03 (m, 1H), 7.96-7.91 (m,1H), 4.64-4.59 (m, 1H), 3.78-3.74 (m, 1H), 2.83-2.78 (m, 2H), 2.43-2.39(m, 2H); MS (m/e) 422.58 MH⁺.

II-58:N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.48 (s, 1H), 12.11 (s, 1H), 8.55 (s, 1H),8.45 (dd, J=3.0, 0.6 Hz, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 8.16 (br s,1H), 7.99 (dd, J=8.9, 0.6 Hz, 1H), 7.62 (dd, J=8.9, 3.0 Hz, 1H), 3.97(s, 6H); LRMS (M+H) m/z 382.66.

II-59:N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.47 (s, 1H), 12.25 (s, 1H), 8.80 (ddd,J=4.9, 1.7, 1.0 Hz, 1H), 8.55-8.54 (m, 1H), 8.49 (s, 1H), 8.32 (s, 1H),8.16 (d, J=1.5 Hz, 1H), 8.06 (ddd, J=8.1, 1.2, 1.2 Hz, 1H), 7.97 (ddd,J=7.7, 7.7, 1.8 Hz, 1H), 7.45 (ddd, J=7.4, 4.9, 1.3 Hz, 1H), 4.67 (hept,J=6.7 Hz, 1H), 1.54 (d, J=6.7 Hz, 6H); LRMS (M+H) m/z 380.65.

II-60:N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, Chloroform-d) δ 12.40 (s, 1H), 10.38 (br s, 1H), 8.72(ddd, J=4.9, 1.8, 1.0 Hz, 1H), 8.46 (s, 1H), 8.17 (s, 2H), 8.09-8.06 (m,2H), 7.77 (ddd, J=8.0, 7.5, 1.8 Hz, 1H), 7.26-7.21 (m, 1H, partiallyoverlapped with CHCl₃), 4.31 (t, J=6.7 Hz, 2H), 3.74-3.70 (m, 4H), 2.91(t, J=6.7 Hz, 2H), 2.55-2.52 (m, 4H); LRMS (M+H) m/z 451.75

II-61:N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.49 (br s, 1H), 12.24 (s, 1H), 8.80 (br d,J=4.9 Hz, 1H), 8.53 (s, 1H), 8.35 (v br s, 2H), 8.34 (s, 1H), 8.04 (d,J=8.0 Hz, 1H), 7.97 (ddd, J=7.5, 7.5, 1.7 Hz, 1H), 7.45 (ddd, J=7.2,5.0, 1.4 Hz, 1H), 4.36 (t, J=6.5 Hz, 2H), 3.40 (br s, 2H), 2.81 (t,J=6.5 Hz, 2H), 2.51 (s, partially overlapped with DMSO, 2H), 2.35 (br s,4H), 2.18 (s, 3H); LRMS (M+H) m/z 464.74.

II-66:2-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.21 (s, 1H), 8.78-8.76 (m,1H), 8.49 (s, 2H), 8.30 (s, 1H), 8.12 (s, br, 1H), 8.03-7.92 (m, 2H),7.46-7.41 (m, 1H), 4.44 (t, J=6.7 Hz, 2H), 4.13 (q, J=10.8 Hz, 2H), 4.04(t, J=6.7 Hz, 2H); LCMS (m/z): 464.11 (MH⁺).

II-67:(2-(1H-pyrazol-4-yl)thiazol-4-yl)(2-((1s,3s)-3-ethoxycyclobutyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone

¹HNMR (300 MHz, MeOD-d4) δ 8.28 (s, 1H), 8.17 (s, 1H), 7.92 (m, 1H),4.48-4.37 (m, 1H), 4.06-4.02 (m, 2H), 3.95-3.87 (m, 1H), 2.87-2.78 (m,4H), 2.48-2.39 (m, 2H), 2.10-2.04 (m, 2H), 1.21 (t, J=6.7 Hz, 3H); LCMS(m/z): 399.21 (MH⁺).

II-68: R927583(2-(1H-pyrazol-4-yl)thiazol-4-yl)(2-((1s,3s)-3-ethoxycyclobutyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanoneas TFA salt

¹HNMR (300 MHz, MeOD-d4) δ 8.17 (s, br, 3H), 7.92 (s, 1H), 4.44-4.37 (m,1H), 4.02-3.89 (m, 4H), 3.49 (q, J=6.7 Hz, 2H), 2.83-2.53 (m, 6H), 2.07(s, br, 2H), 1.21 (t, J=6.7 Hz, 3H), 4.13 (q, J=10.8 Hz, 2H).

II-69: R927597:(2-(1H-pyrazol-4-yl)thiazol-4-yl)(1-(3-ethoxycyclobutyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanoneas TFA salt

63:37 mixture of regioisomers with R927583 (II-68, above).

II-70:N-(3-carbamoyl-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 11.25 (s, 1H), 8.40 (s, 1H),8.39 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.55 (s, 1H),4.65-4.54 (m, 1H), 3.87-3.78 (m, 1H), 3.40 (q, J=6.7 Hz, 2H), 2.83-2.74(m, 2H), 2.47-2.37 (m, 2H), 1.13 (t, J=6.7 Hz, 2H); LCMS (m/z): 402.20(MH⁺).

II-71:N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fuoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

LCMS (m/z): 584.33 (MH⁺).

II-72:N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.75-8.73 (m, 1H), 8.49-8.46(m, 2H), 8.36 (s, 1H), 8.07-8.04 (m, 1H), 7.97-7.91 (m, 1H), 7.44-7.39(m, 1H), 4.68-4.57 (m, 1H), 3.90-3.80 (m, 1H), 3.42 (q, J=6.7 Hz, 2H),2.85-2.73 (m, 2H), 2.45-2.42 (m, 2H), 1.15 (t, J=6.7 Hz, 2H); LCMS(m/z): 454.22 (MH⁺).

II-73:N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamideas formate salt

LCMS (m/z): 454.15 (MH⁺).

II-74:N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.43 (s, 1H), 8.55 (s, 1H),8.36 (s, 1H), 8.29 (s, 1H), 4.77-4.66 (m, 1H), 3.91-3.81 (m, 1H), 3.42(q, J=6.7 Hz, 2H), 2.88-2.79 (m, 2H), 2.47-2.37 (m, 2H), 1.15 (t, J=6.7Hz, 2H); LCMS (m/z): 427.24 (MH⁺).

II-75:N-(3-(1,3,4-oxadiazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.41 (s, 1H), 8.56 (s, 1H),8.36 (s, 1H), 4.71-4.59 (m, 1H), 4.02-3.92 (m, 2H), 3.53-3.44 (m, 2H),2.07-2.03 (m, 4H); LCMS (m/z): 413.13 (MH⁺).

II-76:N-(1-((1,3-cis)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.18 (s, 1H), 8.75 (d, J=5.1Hz, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 8.04(d, J=8.1 Hz, 1H), 7.93 (t, J=8.7 Hz, 1H), 7.42 (t, J=6.6 Hz, 1H), 4.58(p, J=7.8 Hz, 1H), 3.89 (p, J=7.5 Hz, 1H), 3.63 (p, J=6.0 Hz, 1H),2.85-2.76 (m, 2H), 2.43-2.36 (m, 2H), 1.10 (d, J=6.0 Hz, 6H); LCMS:purity: 100%; MS (m/e): 450.19 (MH+).

II-77:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate bis-potassium salt

To a mixture of(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate (300 mg) in acetonitrile (2 mL) and water (1 mL), was added1.0 N potassium hydroxide aqueous solution (1.1 mL, 2 eq.) Aftersonicating for five minutes, the solution was lyophilized for 24 hours.The resulting powder was suspended in water (1 mL) and isopropanol (5mL). The mixture was stirred at 70° C. for five minutes until a clearsolution formed. The solution was cooled to room temperature. Theresulting precipitate was collected through filtration, washed withisopropanol (3×1 mL) and dried under high vacuum at room temperature for24 hours to give potassium salt as a white solid (280 mg).

¹H NMR (300 MHz, Deuterium Oxide) δ 7.83 (d, 1H), 7.80 (s, 1H), 7.64 (s,1H), 7.42 (s, 1H), 7.41 (m, 1H), 7.29 (s, 1H), 7.17 (d, J=7.2 Hz, 1H),6.89 (m, 1H), 5.57 (d, J=8.1 Hz, 2H), 4.13 (m, 1H), 3.91 (t, J=7.8 Hz,1H), 3.49 (q, J=7.2 Hz, 2H), 2.83 (m, 2H), 2.19 (m, 2H), 1.14 (t, J=7.2Hz, 3H); LCMS: purity: 100%; MS (m/e): 546.23 (MH+).

II-78:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate calcium salt

To a mixture of(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate (309 mg) in acetonitrile (2 mL) and water (1 mL), was addedcalcium hydroxide (42 mg, 1 eq.). After sonicating for five minutes, thereaction mixture was lyophilized for 24 hours. The resulting powder wassuspended in water (1 mL) and isopropanol (5 mL). The mixture wasstirred at 70° C. for five minutes and then cooled to room temperature.The resulting precipitate was collected through filtration, washed withisopropanol (3×1 mL) and dried under high vacuum at room temperature for24 hours to give calcium salt as a white solid (300 mg).

LCMS: purity: 95.41%; MS (m/e): 546.22 (MH+).

II-79:N-(1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.17 (s, 1H), 8.74 (d, J=5.1Hz, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 8.03(d, J=7.8 Hz, 1H), 7.93 (t, J=8.4 Hz, 1H), 7.40 (t, J=6.6 Hz, 1H), 5.06(s, 1H), 5.04 (p, J=7.8 Hz, 1H), 1.37 (s, 3H); LCMS: purity: 100%; MS(m/e): 422.22 (MH+).

II-80:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-H-pyrazol-1-yl)methylphosphate bis-ammonium salt

To a mixture of(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate (200 mg) in acetonitrile (1 mL) and water (1 mL), was added2.0 N ammonia in methanol solution (0.37 mL, 2 eq.). After sonicatingfor five minutes, the solution was lyophilized for 24 hours. Theresulting powder was suspended in water (0.5 mL) and isopropanol (3 mL).The resulting precipitate was collected through filtration, washed withisopropanol (3×1 mL) and dried under high vacuum at room temperature for24 hours to give ammonium salt (180 mg) as a white solid.

¹H NMR (300 MHz, Deuterium Oxide) δ 7.71 (s, 2H), 7.56 (s, 1H), 7.33 (m,2H), 7.19 (s, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.82 (t, J=5.7 Hz, 1H), 5.53(d, J=7.8 Hz, 2H), 4.08 (p, J=7.8 Hz, 1H), 3.89 (m, 1H), 3.48 (q, J=7.2Hz, 2H), 2.79 (m, 2H), 2.13 (m, 2H), 1.13 (t, J=7.2 Hz, 3H); LCMS:purity: 100%; MS (m/e): 546.15 (MH+).

II-81:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate bis-lysine salt

To a mixture of(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate (200 mg) in acetonitrile (1 mL) and water (1 mL), was addedL-lysine (107 mg, 2 eq.). After sonicating for five minutes, thesolution was lyophilized for 24 hours. The resulting powder wassuspended in water (0.5 mL) and isopropanol (3 mL). The resultingprecipitate was collected through filtration, washed with isopropanol(3×1 mL) and dried under high vacuum at room temperature for 24 hours togive bis-lysine salt (200 mg) as a white solid.

¹H NMR (300 MHz, Deuterium Oxide) δ 7.82 (m, 1H), 7.79 (s, 1H), 7.63 (s,1H), 7.41 (s, 1H), 7.39 (m, 1H), 7.28 (s, 1H), 7.16 (d, J=9.0 Hz, 1H),6.88 (m, 1H), 5.56 (d, J=8.1 Hz, 2H), 4.12 (m, 1H), 3.90 (t, J=7.8 Hz,1H), 3.61 (t, J=5.7 Hz, 2H), 3.48 (q, J=6.9 Hz, 2H), 2.88 (t, J=7.5 Hz,4H), 2.82 (m, 2H), 2.16 (m, 2H), 1.80-1.72 (m, 4H), 1.63-1.53 (m, 4H),1.42-1.29 (m, 4H), 1.13 (t, J=7.2 Hz, 3H); LCMS: purity: 100%; MS (m/e):546.15 (MH+).

II-82:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate bis-arginine salt

To a mixture of(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate (200 mg) in acetonitrile (1 mL) and water (1 mL), was addedL-arginine (128 mg, 2 eq.). After sonicating for five minutes, thesolution was lyophilized for 24 hours. The resulting powder wassuspended in water (0.5 mL) and isopropanol (3 mL). The resultingprecipitate was collected through filtration, washed with isopropanol(3×1 mL) and dried under high vacuum at room temperature for 24 hours togive bis-arginine salt (200 mg) as a white solid. The salt wasre-dissolved in water (0.5 mL) and acetone (8 mL). After heating at 50°C. for 10 minutes, the solution was cooled to room temperature. Theresulting precipitate was collected through filtration, washed withacetone and dried under high vacuum at room temperature for 24 hours togive bis-arginine salt (120 mg) as a white solid.

¹H NMR (300 MHz, Deuterium Oxide) δ 7.88 (d, J=5.4 Hz, 1H), 7.84 (s,1H), 7.68 (s, 1H), 7.46 (s, 1H), 7.41 (d, J=6.3 Hz, 1H), 7.33 (s, 1H),7.20 (d, J=8.1 Hz, 1H), 6.92 (m, 1H), 5.57 (d, J=8.7 Hz, 2H), 4.15 (t,J=8.7 Hz, 1H), 3.91 (t, J=6.6 Hz, 1H), 3.62 (t, J=6.0 Hz, 2H), 3.49 (q,J=7.2 Hz, 2H), 3.08 (t, J=6.9 Hz, 4H), 2.82 (m, 2H), 2.11 (m, 2H),1.80-1.72 (m, 4H), 1.63-1.44 (m, 4H), 1.14 (t, J=7.2 Hz, 3H); LCMS:purity: 100%; MS (m/e): 546.15 (MH+).

II-83:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

N-(1-((1,3-Cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(59 g) and cesium carbonate (88 g, 2 eq.) were suspended indimethylformamide (500 mL), di-tert-butyl (chloromethyl) phosphate (53g, 1.5 eq.) was added to the reaction and the mixture allowed to stir atroom temperature for 16-20 hours. The reaction mixture was diluted withwater (1 L) and extracted with ethyl acetate (2×800 mL). The combinedorganic layers were evaporated at room temperature and purified usingthe Torrent Combiflash®Rf column chromatography (ethyl acetate inhexanes, 20 to 100%) to give the prodrug ester as a colorless oil (85 g,95% yield). LCMS: purity: 100%; MS (m/e): 658.38 (MH+).

Di-tert-butyl((4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate (85 g) was dissolved in anhydrous dichloromethane (700 mL),the resulting solution was cooled to 0° C. and trifluoroacetic acid (150mL) was added drop-wise. The reaction mixture was stirred at 0° C. for 6hours, when LC-MS analysis showed full conversion to the acid, thesolution was evaporated on a rotary evaporator at room temperature. Theresidue was dried further under high vacuum at room temperature for 24hours to give a light yellow semi-solid as the acid and usedsubsequently to form salts.

(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate (100 mg) was stirred overnight at 50° C. in acetone(10 mL) and water (0.5 mL). The cloudy solution was cooled to roomtemperature. The white precipitate was collected by filtration, washedwith acetone and dried under high vacuum at room temperature for 24hours (90 mg).

¹H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 8.61(s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 8.04 (d, J=8.1 Hz,1H), 7.93 (t, J=6.9 Hz, 1H), 7.40 (t, J=6.0 Hz, 1H), 5.90 (d, J=11.1 Hz,2H), 4.60 (t, J=8.4 Hz, 1H), 3.83 (t, J=6.6 Hz, 1H), 3.41 (q, J=6.9 Hz,2H), 2.80 (m, 2H), 2.42 (m, 2H), 1.13 (t, J=6.9 Hz, 3H); LCMS: purity:100%; MS (m/e): 546.15 (MH+).

II-84:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate Tris salt

To a mixture of(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate (118 mg) in acetonitrile (1 mL) and water (1 mL), was addedTris(hydroxymethyl)aminomethane (52 mg, 2 eq.). After sonicating forfive minutes, the solution was lyophilized for 24 hours. The resultingpowder was suspended in water (0.5 mL) and acetone (5 mL). The solutionwas stirred at 50° C. for 30 minutes and cooled to room temperature.After one week at room temperature, the resulting precipitate wascollected through filtration, washed with acetone (3×1 mL) and driedunder high vacuum at room temperature for 24 hours to give mono-Trissalt (120 mg) as a white solid.

¹H NMR (300 MHz, Deuterium Oxide) δ 7.83 (m, 2H), 7.65 (s, 1H), 7.43 (s,1H), 7.40 (d, J=7.5 Hz, 1H), 7.30 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.90(t, J=6.0 Hz, 1H), 5.57 (d, J=8.1 Hz, 2H), 4.13 (t, J=7.5 Hz, 1H), 3.91(t, J=6.9 Hz, 1H), 3.60 (s, 6H), 3.49 (q, J=6.9 Hz, 2H), 2.82 (m, 2H),2.18 (m, 2H), 1.14 (t, J=6.9 Hz, 3H); LCMS: purity: 100%; MS (m/e):546.16 (MH+).

II-85:(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate triethylamine salt

¹H NMR (300 MHz, Deuterium Oxide) δ 7.81 (d, 1H), 7.77 (s, 1H), 7.61 (s,1H), 7.39 (s, 2H), 7.26 (s, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.87 (t, J=6.6Hz, 1H), 5.55 (d, J=9.0 Hz, 2H), 4.11 (p, J=8.4 Hz, 1H), 3.90 (p, J=7.1Hz, 1H), 3.48 (q, J=7.1 Hz, 2H), 3.05 (q, J=7.4 Hz, 6H), 2.80 (m, 2H),2.15 (m, 2H), 1.13 (t, J=7.3 Hz, 12H); LCMS: purity: 100%; MS (m/e):546.15 (MH+).

II-86:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d6) δ 13.45 (s, 1H), 11.84 (s, 1H), 9.04 (s, 1H),8.53 (s, 2H), 8.32-8.30 (m, 2H), 8.23 (d, J=8.1 Hz, 1H), 8.12 (s, 1H),4.65 (p, J=7.5 Hz, 1H), 3.84 (p, J=6.6 Hz, 1H), 3.41 (q, J=7.0 Hz, 2H),2.82 (m, 2H), 2.42 (m, 2H), 1.13 (t, J=7.0 Hz, 3H); LCMS: purity:94.79%; MS (m/e): 502.27 (MH+).

II-87:N-(1-(3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

LCMS: purity: 91.70%; MS (m/e): 422.16 (MH+).

II-88:N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 12.26 (s, 1H), 8.85-8.82 (m,2H), 8.51 (s, 1H), 8.35 (s, 1H), 8.13-8.10 (m, 2H), 8.02 (t, J=8.7 Hz,1H), 7.93 (t, J=59.1 Hz, 1H), 7.55 (dd, J=7.5, 4.9 Hz, 1H); LCMS:purity: 100%; MS (m/e): 388.10 (MH+).

II-89:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(3-(trifuoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d6) δ 13.43 (s, 1H), 11.68 (s, 1H), 9.05 (d, J=4.8Hz, 1H), 8.48 (m, 1H), 8.38 (d, J=7.9 Hz, 1H), 8.28 (s, 3H), 7.66 (dd,J=8.1, 4.9 Hz, 1H), 4.62 (p, J=8.1 Hz, 1H), 3.83 (p, J=7.2 Hz, 1H), 3.40(q, J=7.0 Hz, 2H), 2.82-2.73 (m, 2H), 2.45-2.38 (m, 2H), 1.12 (t, J=7.0Hz, 3H); LCMS: purity: 92.15%; MS (m/e): 504.22 (MH+).

II-90:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.93 (s, 1H), 8.60 (s, 1H),8.38-8.33 (m, 3H), 8.19 (t, J=7.9 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J=7.6Hz, 1H), 4.64 (p, J=8.4 Hz, 1H), 3.84 (p, J=7.1 Hz, 1H), 3.41 (q, J=7.0Hz, 2H), 2.86-2.77 (m, 2H), 2.42-2.38 (m, 2H), 1.13 (t, J=7.0 Hz, 3H);LCMS: purity: 100%; MS (m/e): 504.22 (MH+).

II-91:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.67 (s, 1H), 8.59 (d, J=5.0Hz, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.90 (td,J=7.8, 1.8 Hz, 1H), 7.36 (dd, J=4.8, 1.2 Hz, 1H), 4.61 (p, J=7.5 Hz,1H), 3.83 (p, J=6.9 Hz, 1H), 3.41 (q, J=7.0 Hz, 2H), 2.82-2.76 (m, 2H),2.43-2.40 (m, 2H), 1.13 (t, J=7.0 Hz, 3H); LCMS: purity: 100%; MS (m/e):504.22 (MH+).

II-92:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.19 (s, 1H), 11.83 (s, 1H), 8.63 (d, J=5.1Hz, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.99 (m,1H), 7.92 (td, J=7.5, 1.2 Hz, 1H), 7.39 (t, J=6.0 Hz, 1H), 4.61 (p,J=8.1 Hz, 1H), 3.83 (p, J=6.9 Hz, 1H), 3.41 (q, J=7.1 Hz, 2H), 2.85-2.76(m, 2H), 2.68 (s, 3H), 2.43-2.37 (m, 2H), 1.13 (t, J=6.9 Hz, 3H); LCMS:purity: 100%; MS (m/e): 450.25 (MH+).

II-93:2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H), 11.61 (s, 1H), 8.57 (d, J=4.8Hz, 1H), 8.53 (s, 1H), 8.33 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.91 (td,J=7.7, 1.8 Hz, 1H), 7.37 (dd, J=7.5, 1.2 Hz, 1H), 4.61 (p, J=7.5 Hz,1H), 3.83 (p, J=6.9 Hz, 1H), 3.41 (q, J=7.0 Hz, 2H), 2.85-2.76 (m, 2H),2.56 (br, 6H), 2.43-2.37 (m, 2H), 1.13 (t, J=7.0 Hz, 3H); LCMS: purity:100%; MS (m/e): 464.23 (MH+).

II-94:2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.22 (s, 1H), 8.79 (dd,J=4.9, 1.5 Hz, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.31 (s, 1H), 8.11 (s,1H), 8.02 (d, J=6.6 Hz, 1H), 7.96 (td, J=8.1, 1.8 Hz, 1H), 7.47 (dd,J=8.7, 1.5 Hz, 1H), 5.29 (q, J=9.0 Hz, 2H); LCMS: purity: 100%; MS(m/e): 420.15 (MH+).

II-95:N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.89 (s, 1H), 8.72 (s, 1H),8.66 (d, J=4.2 Hz, 1H), 8.54 (s, 1H), 8.14-8.10 (m, 2H), 7.99 (t, J=8.1Hz, 1H), 7.94 (t, J=58.8 Hz, 1H), 7.50 (dd, J=6.0, 1.2 Hz, 1H); LCMS:purity: 100%; MS (m/e): 456.10 (MH+).

II-96:N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.20 (s, 1H), 11.93 (s, 1H), 8.88 (s, 1H),8.72 (d, J=5.4 Hz, 1H), 8.37 (s, 1H), 8.13 (d, J=8.1 Hz, 1H), 8.01 (t,J=7.5 Hz, 2H), 7.94 (t, J=58.8 Hz, 1H), 7.54 (t, J=6.3 Hz, 1H), 2.69 (s,3H); LCMS: purity: 100%; MS (m/e): 402.14 (MH+).

II-97:N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.84 (d, J=3.7 Hz, 2H), 8.61(s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.12 (d, J=8.1 Hz, 1H), 8.01 (t,J=8.1 Hz, 1H), 7.94 (t, J=59.1 Hz, 1H), 7.54 (ddd, J=7.5, 4.9, 1.3 Hz,1H), 5.31 (q, J=9.0 Hz, 2H); LCMS: purity: 100%; MS (m/e): 470.15 (MH+).

II-98:2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.02 (s, 1H), 8.84 (m, 2H),8.48 (s, 1H), 8.41 (s, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.02 (t, J=8.1 Hz,1H), 7.94 (t, J=58.5 Hz, 2H), 7.55 (ddd, J=7.5, 4.9, 1.3 Hz, 1H); LCMS:purity: 100%; MS (m/e): 438.09 (MH+).

II-99:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.59 (s, 1H), 8.36-8.32 (m,2H), 8.18 (t, J=7.9 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 4.65(p, J=8.1 Hz, 1H), 3.85 (p, J=6.5 Hz, 1H), 3.41 (q, J=7.0 Hz, 2H), 2.82(m, 2H), 2.42 (m, 2H), 1.14 (t, J=7.2 Hz, 3H); LCMS: purity: 94.50%; MS(m/e): 518.33 (MH+).

II-100:2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 11.88 (s, 1H), 8.68-8.65 (m,2H), 8.32 (s, 1H), 8.05-7.92 (m, 3H), 7.44 (t, J=5.8 Hz, 1H), 5.29 (q,J=9.1 Hz, 2H), 2.68 (s, 3H); LCMS: purity: 100%; MS (m/e): 434.26 (MH+).

II-101:N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 11.68 (s, 1H), 9.24 (d, J=1.5Hz, 1H), 8.80 (dd, J=2.6, 1.6 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.54 (s,1H), 8.51 (s, 1H), 8.30 (s, 1H), 8.11 (d, J=1.7 Hz, 1H), 5.33 (d, J=7.0Hz, 1H), 4.52 (p, J=7.2 Hz, 1H), 3.97 (h, J=6.6 Hz, 1H), 2.84-2.75 (m,2H), 2.43-2.39 (m, 2H); LCMS: purity: 96.50%; MS (m/e): 409.16 (MH+).

II-102:N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 11.91 (s, 1H), 8.98 (d, J=4.9Hz, 2H), 8.51 (s, 2H), 8.30 (s, 1H), 8.10 (s, 1H), 7.49 (t, J=4.9 Hz,1H), 4.65 (p, J=8.5 Hz, 1H), 3.85 (p, J=7.3 Hz, 1H), 3.41 (q, J=7.0 Hz,2H), 2.85-2.76 (m, 2H), 2.43 (m, 2H), 1.14 (t, J=7.0 Hz, 3H); LCMS:purity: 100%; MS (m/e): 437.19 (MH+).

II-103:2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 570 [M+H]⁺

II-105:N-(1-(dimethylcarbomoyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 529 [M+H]⁺

II-107:2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 638 [M+H]⁺

II-109: 6N-(1-(2-ethoxyethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.40 (s, 1H), 11.43 (s, 1H), 8.48 (s, 1H),8.45 (s, 1H), 8.31 (s, 1H), 8.11 (d, J=3.3 Hz, 1H), 7.78 (d, J=3.3 Hz,1H), 7.65-7.48 (m, 2H), 4.36 (t, J=5.2 Hz, 2H), 3.77 (dd, J=5.7, 4.9 Hz,2H), 3.45 (q, J=7.0 Hz, 2H), 1.07 (t, J=7.0 Hz, 3H).

MS (ESI) (m/z): 416 [M+H]⁺

II-111:2-(1H-pyrazol-4-yl)-N-(1-(tetrahydro-2H-pyran-4-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 428 [M+H]⁺

II-113:N-(1-(2-(2-methoxyethoxy)ethyl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H),8.11 (d, J=3.3 Hz, 1H), 7.78 (d, J=3.3 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H),3.82 (dd, J=5.7, 4.9 Hz, 2H), 3.56-3.52 (m, 2H), 3.43-3.39 (m, 2H), 3.20(s, 3H).

MS (ESI) (m/z): 446 [M+H]⁺

II-115:2-(1H-pyrazol-4-yl)-N-(1-(tetrahydrofuran-3-yl)-3-(thiazol-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (s, 1H), 11.45 (s, 1H), 8.46 (s, 1H),8.30 (s, 1H), 8.12 (d, J=3.3 Hz, 1H), 7.79 (d, J=3.3 Hz, 1H), 5.16 (dq,J=8.5, 4.5 Hz, 1H), 4.08-3.99 (m, 1H), 3.98 (d, J=4.9 Hz, 2H), 3.82 (td,J=8.3, 5.8 Hz, 1H), 2.47-2.39 (m, 1H), 2.30 (dddd, J=13.3, 7.7, 5.8, 3.7Hz, 1H).

MS (ESI) (m/z): 414 [M+H]⁺

II-117:N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.45 (s, 1H), 12.18 (s, 1H), 8.74 (ddd,J=4.9, 1.8, 1.0 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 2H), 8.27 (s, 1H), 7.99(dt, J=8.0, 1.2 Hz, 1H), 7.91 (ddd, J=8.0, 7.4, 1.8 Hz, 1H), 7.39 (ddd,J=7.4, 4.9, 1.3 Hz, 1H), 4.22 (t, J=6.4 Hz, 2H), 2.83 (t, J=6.4 Hz, 2H),2.52-2.44 (m, 4H), 0.90 (t, J=7.1 Hz, 6H).

MS (ESI) (m/z): 437 [M+H]⁺

II-118:N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.75 (ddd, J=4.9, 1.8, 1.0Hz, 1H), 8.47 (s, 1H), 8.30 (s, 2H), 8.28 (s, 1H), 7.99 (dt, J=8.0, 1.2Hz, 1H), 7.91 (ddd, J=8.0, 7.4, 1.8 Hz, 1H), 7.40 (ddd, J=7.4, 5.0, 1.3Hz, 1H), 4.58-4.54 (m, 1H), 4.45-4.42 (m, 1H), 4.38 (t, J=5.3 Hz, 2H),3.88 (t, J=5.3 Hz, 2H), 3.73-3.68 (m, 1H), 3.65-3.60 (m, 1H).

MS (ESI) (m/z): 428 [M+H]⁺

II-120:N-(1-benzyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, 1H), 12.21 (s, 1H), 8.75 (ddd,J=5.0, 1.8, 1.0 Hz, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 8.26 (s, 1H), 8.10(s, 1H), 7.99 (dt, J=8.0, 1.1 Hz, 1H), 7.91 (ddd, J=8.1, 7.5, 1.8 Hz,1H), 7.47-7.25 (m, 6H), 5.44 (s, 2H).

MS (ESI) (m/z): 428 [M+H]⁺

II-121:N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (s, 1H), 12.18 (s, 1H), 8.75 (ddt,J=4.9, 1.7, 0.9 Hz, 1H), 8.47 (d, J=0.7 Hz, 1H), 8.27 (d, J=0.9 Hz, 1H),8.04 (dd, J=8.0, 1.0 Hz, 1H), 7.97-7.88 (m, 1H), 7.45-7.37 (m, 1H),5.08-4.77 (m, 1H), 2.63-2.35 (m, 4H), 1.82 (dtd, J=10.5, 7.2, 2.2 Hz,2H).

MS (ESI) (m/z): 392 [M+H]⁺

II-122:N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.43 (s, 1H), 12.21 (s, 1H), 8.75 (ddd,J=4.9, 1.8, 1.0 Hz, 1H), 8.48 (s, 2H), 8.27 (s, 1H), 8.13 (s, 1H), 7.99(dt, J=8.1, 1.1 Hz, 1H), 7.95-7.84 (m, 1H), 7.38 (ddd, J=7.5, 4.9, 1.2Hz, 1H), 6.11 (tt, J=54.9, 3.7 Hz, 1H), 4.40 (t, J=5.2 Hz, 2H), 3.96 (t,J=5.3 Hz, 2H), 3.72 (td, J=15.1, 3.8 Hz, 2H).

MS (ESI) (m/z): 446 [M+H]⁺

II-123:N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 422 [M+H]⁺

II-125:N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 409 [M+H]⁺

II-127:N-(1-((1s,3s)-3-(ethoxy-d5)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, 1H), 12.19 (s, 1H), 8.75 (ddd,J=5.0, 1.8, 1.0 Hz, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.11(s, 1H), 8.03 (dt, J=8.1, 1.1 Hz, 1H), 7.91 (ddd, J=8.0, 7.5, 1.8 Hz,1H), 7.39 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 4.57 (tt, J=9.0, 7.4 Hz, 1H),3.79 (tt, J=7.7, 6.6 Hz, 1H), 2.78 (dddd, J=9.9, 9.0, 4.8, 2.7 Hz, 2H),2.41 (dddd, J=10.6, 9.0, 6.7, 2.8 Hz, 2H).

MS (ESI) (m/z): 441 [M+H]⁺

II-128:N-(1-(diethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, 1H), 12.20 (s, 1H), 8.81 (ddd,J=5.0, 1.7, 1.0 Hz, 1H), 8.76 (s, 1H), 8.34 (s, 1H), 8.32-8.16 (m, 2H),8.11-7.97 (m, 2H), 7.52 (ddd, J=7.3, 4.9, 1.4 Hz, 1H), 3.55 (d, J=8.8Hz, 4H), 1.27 (t, J=6.9 Hz, 6H). MS (ESI) (m/z): 437 [M+H]⁺

II-129:N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 12.21 (s, 1H), 8.83 (ddd, J=5.0, 1.8, 1.0Hz, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.33-8.23 (m, 2H), 8.11 (dt, J=8.0,1.1 Hz, 1H), 8.02 (td, J=7.8, 1.8 Hz, 1H), 7.54 (ddd, J=7.5, 4.9, 1.3Hz, 1H), 3.81 (s, 4H), 3.72 (dd, J=5.6, 3.6 Hz, 4H).

MS (ESI) (m/z): 451 [M+H]⁺

II-130:N-(1-((1s,3s)-3-(2-fluoroethoxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (s, 1H), 12.18 (s, 1H), 8.75 (ddd,J=5.0, 1.8, 1.0 Hz, 1H), 8.53-8.47 (m, 1H), 8.46 (s, 1H), 8.27 (s, 1H),8.11 (s, 1H), 8.04 (dt, J=8.0, 1.1 Hz, 1H), 7.92 (ddd, J=8.1, 7.5, 1.8Hz, 1H), 7.41 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 4.68-4.54 (m, 2H),4.52-4.45 (m, 1H), 3.90 (tt, J=7.7, 6.5 Hz, 1H), 3.68-3.63 (m, 1H),3.60-3.54 (m, 1H), 2.82 (dddd, J=11.6, 7.3, 6.0, 2.7 Hz, 2H), 2.53-2.39(m, 2H).

MS (ESI) (m/z): 454 [M+H]⁺

II-132:N-(1-(3-fuorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 408 [M+H]⁺

II-134:N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.77 (ddd, J=5.0, 1.8, 1.0Hz, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 8.06 (dt, J=8.0, 1.1 Hz, 1H), 7.95(td, J=7.7, 1.8 Hz, 1H), 7.44 (ddd, J=7.5, 4.9, 1.3 Hz, 1H), 5.07 (qd,J=8.4, 6.5 Hz, 1H), 3.28-3.14 (m, 4H).

MS (ESI) (m/z): 428 [M+H]⁺

II-136:N-(3-cyano-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 10.30 (s, 1H), 8.32 (s, 1H),8.23 (s, 1H), 5.34 (d, J=7.0 Hz, 1H), 4.50 (tt, J=9.1, 7.3 Hz, 1H), 3.95(q, J=7.0 Hz, 1H), 2.83-2.69 (m, 2H), 2.33 (dddd, J=10.9, 9.1, 6.7, 2.7Hz, 2H).

MS (ESI) (m/z): 356 [M+H]⁺

II-137:N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H), 8.25 (s, 2H), 8.15 (s, 1H),3.94 (s, 3H).

MS (ESI) (m/z): 300 [M+H]⁺

II-138:N-(3-cyano-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.29 (s, 1H), 8.22 (s, 2H), 8.06 (s, 1H),8.05-7.54 (m, 2H), 4.54-4.28 (m, 1H), 3.92 (q, J=6.9 Hz, 1H), 3.84-3.68(m, 2H), 2.67 (q, J=8.6, 7.9 Hz, 2H), 2.34-2.17 (m, 2H), 1.15 (t, J=7.1Hz, 3H).

MS (ESI) (m/z): 384 [M+H]⁺

II-140:N-(3-(3-fluoropyridin-2-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

MS (ESI) (m/z): 496 [M+H]⁺

II-141:2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((trans)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 12.18 (s, 1H), 8.76 (d, J=4.8Hz, 1H), 8.49 (s, 2H), 8.28 (s, 1H), 8.10 (m, 2H), 7.94 (m, 1H), 7.42(t, J=6.6 Hz, 1H), 5.09 (m, 1H), 4.54 (m, 1H), 4.05 (m, 2H), 2.71 (m,2H), 2.60 (m, 2H). LCMS: purity: 88.96%. MS (m/e): 489.48 (MH⁺).

II-143:N-(1-((trans)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 12.18 (s, 1H), 8.74 (d, J=4.8Hz, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.98(m, 1H), 7.91 (t, J=7.8 Hz, 1H), 7.39 (t, J=6.0 Hz, 1H), 4.66 (d, J=4.2Hz, 1H), 4.25 (t, J=11.1 Hz, 1H), 3.53 (m, 1H), 2.02 (m, 2H), 1.90 (m,4H), 1.37 (m, 2H). LCMS: purity: 94.52%. MS (m/e): 435.51 (MH⁺).

II-147:N-(1-((cis)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.36 (s, 1H), 12.14 (s, 1H), 8.69 (d, J=4.8Hz, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.89 (m, 2H), 7.45(m, 2H), 7.35 (m, 1H), 4.77 (m, 1H), 3.93 (m, 2H), 3.41 (m, 2H), 2.12(m, 2H), 1.98 (m, 2H), 1.80 (m, 2H), 1.50 (t, J=8.4 Hz, 3H).

LCMS: purity: 96.91%. MS (m/e): 449.53 (MH⁺).

II-149:N-(1-((cis)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 12.18 (s, 1H), 8.75 (t, J=0.9 Hz, 1H), 8.50(d, J=15.6 Hz, 1H), 8.27 (m, 3H), 7.95 (m, 2H), 7.38 (m, 1H), 4.80 (m,1H), 4.21 (m, 1H), 3.60 (m, 1H), 2.19 (m, 2H), 2.12 (m, 2H), 1.81 (m,2H). LCMS: purity: 95.63%. MS (m/e): 421.48 (MH⁺).

II-151:N-(1-((trans)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.73 (t, J=1.8 Hz, 1H), 8.44(s, 1H), 8.27 (m, 3H), 7.92 (m, 2H), 7.40 (m, 1H), 4.98 (m, 1H), 4.38(m, 1H), 3.44 (m, 1H), 2.24 (m, 2H), 2.07 (m, 3H), 1.72 (m, 1H). LCMS:purity: 100%. MS (m/e): 421.48 (MH⁺).

II-153:N-(1-((cis)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.36 (s, 1H), 11.76 (s, 1H), 8.68 (d, J=3.0Hz, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.85(m, 1H), 7.50 (m, 1H), 4.54 (m, 1H), 3.75 (m, 1H), 3.40 (m, 2H), 2.74(m, 2H), 2.42 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). LCMS: purity: 96.80%. MS(m/e): 453.50 (MH⁺).

II-155:N-(1-((cis)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, CDCl₃) δ 12.39 (s, 1H), 8.71 (d, J=3.9 Hz, 1H), 8.47(s, 1H), 8.13 (d, J=8.1 Hz, 1H), 8.07 (s, 1H), 7.78 (t, J=7.8 Hz, 1H),7.56 (m, 2H), 7.25 (t, J=3.9 Hz, 1H), 5.17 (m, 1H), 4.36 (m, 1H), 3.93(m, 1H), 3.64 (m, 1H), 2.76 (t, J=8.7 Hz, 1H), 2.18 (q, J=18.6 Hz, 1H),1.55 (s, 1H), 1.29 (t, J=6.9 Hz, 3H). LCMS: purity: 96.40%. MS (m/e):453.50 (MH⁺).

II-157:N-(1-((cis)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 12.05 (s, 1H), 8.56 (m, 1H),8.52 (s, 1H), 8.49 (s, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 7.90 (t, J=9.9Hz, 1H), 7.53 (m, 1H), 4.61 (m, 1H), 3.83 (m, 1H), 3.42 (m, 2H), 2.81(m, 2H), 2.42 (m, 2H), 1.14 (t, J=7.2 Hz, 3H). LCMS: purity: 100%. MS(m/e): 453.50 (MH⁺).

II-158:N-(1-((cis)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.25 (s, 1H), 11.43 (s, 1H), 8.78 (m, 1H),8.45 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.79 (m, 1H), 7.36 (m, 1H),7.28 (d, J=3.6 Hz, 1H), 4.61 (m, 1H), 3.83 (m, 1H), 3.41 (m, 2H), 2.80(m, 2H), 2.41 (m, 2H), (t, J=6.9 Hz, 3H). LCMS: purity: 100%. MS (m/e):453.50 (MH⁺).

II-160:N-(1-((cis)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 11.58 (s, 1H), 8.50 (s, 1H),8.46 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 8.13 (m, 1H), 7.96 (d, J=2.4Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.63 (m, 1H), 3.83 (m, 1H), 3.40 (m,2H), 2.80 (m, 2H), 2.45 (m, 2H), 1.14 (t, J=6.9 Hz, 3H).

LCMS: purity: 100%. MS (m/e): 453.50 (MH⁺).

II-161:2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((cis)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.43 (s, 1H), 12.18 (s, 1H), 8.76 (t, J=4.2Hz, 1H), 8.48 (t, J=3.0 Hz, 2H), 8.13 (s, 1H), 8.04 (d, J=6.9 Hz, 1H),7.96 (m, 2H), 7.43 (m, 1H), 5.07 (m, 1H), 4.54 (m, 1H), 4.08 (m, 2H),2.74 (m, 2H), 2.61 (m, 2H). LCMS: purity: 97.81%. MS (m/e): 489.48(MH⁺).

II-163:(4-(4-((1-((cis)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 8.72 (m, 1H), 8.60 (s, 1H),8.52 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.89 (m, 1H), 7.50 (m, 1H),5.92 (s, 1H), 5.88 (s, 1H), 4.63 (m, 1H), 3.83 (m, 1H), 3.40 (m, 2H),2.82 (m, 2H), 2.44 (m, 2H), 1.13 (t, J=6.9 Hz, 3H). LCMS: purity:95.89%. MS (m/e): 563.50 (MH⁺).

II-164:(4-(4-((1-((cis)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyldisodium phosphate

¹H NMR (300 MHz, Deuterium Oxide) δ 8.11 (s, 1H), 8.04 (d, J=4.2 Hz,1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.41 (t, J=8.1 Hz, 1H),7.16 (m, 1H), 5.62 (s, 1H), 5.59 (s, 1H), 4.30 (m, 1H), 3.93 (m, 1H),3.50 (m, 2H), 2.85 (m, 2H), 2.26 (m, 2H), 1.12 (t, J=6.9 Hz, 3H).

LCMS: purity: 95.89%. MS (m/e): 563.50 (MH⁺).

II-165:N-(3-(3-fluoropyridin-2-yl)-1-((cis)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.37 (s, 1H), 12.00 (s, 1H), 8.60 (d, J=4.8Hz, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.83(m, 1H), 7.46 (m, 1H), 4.58 (m, 1H), 3.98 (m, 2H), 3.54 (m, 1H), 2.78(m, 2H), 2.44 (m, 2H). LCMS: purity: 96.48%. MS (m/e): 507.47 (MH⁺).

II-167:N-(3-(3-fluoropyridin-2-yl)-1-((trans)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 12.06 (s, 1H), 8.66 (d, J=4.5Hz, 1H), 8.55 (s, 1H), 8.28 (m, 3H), 7.91 (m, 1H), 7.55 (m, 1H), 5.11(m, 1H), 4.52 (m, 1H), 4.05 (m, 2H), 2.71 (m, 2H), 2.48 (m, 2H). LCMS:purity: 95.89%. MS (m/e): 507.47 (MH⁺).

II-169:N-(1-((trans)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H), 12.07 (s, 1H), 8.64 (d, J=3.3Hz, 1H), 8.48 (s, 2H), 8.28 (s, 1H), 8.09 (s, 1H), 7.87 (m, 1H), 7.53(m, 1H), 4.32 (m, 1H), 3.44 (m, 2H), 3.35 (m, 1H), 2.06 (m, 4H), 1.92(m, 2H), 1.38 (m, 2H), 1.10 (t, J=6.9 Hz, 3H). LCMS: purity: 97.81%. MS(m/e): 481.55 (MH⁺).

II-170:N-(3-(6-fluoropyridin-2-yl)-1-((cis)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.37 (s, 1H), 11.53 (s, 1H), 8.49 (d, J=6.9Hz, 1H), 8.24 (m, 4H), 8.08 (m, 1H), 7.93 (m, 1H), 7.16 (d, J=7.5 Hz,1H), 4.60 (m, 1H), 4.00 (m, 3H), 2.78 (m, 2H), 2.46 (m, 2H). LCMS:purity: 100%. MS (m/e): 507.47 (MH⁺).

II-172:N-(3-(6-fluoropyridin-2-yl)-1-((cis)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.44 (s, 1H), 11.58 (s, 1H), 8.53 (s, 1H),8.50 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.10 (m, 1H), 7.95 (d, J=7.5Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 5.32 (m, 1H), 4.50 (m, 1H), 3.96 (m,1H), 2.79 (m, 2H), 2.40 (m, 2H). LCMS: purity: 100%.

MS (m/e): 425.45 (MH⁺).

II-173:(4-(4-((1-((cis)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

¹H NMR (300 MHz, DMSO-d₆) δ 11.59 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H),8.35 (s, 1H), 8.22 (s, 1H), 8.10 (m, 1H), 7.96 (m, 1H), 7.21 (d, J=6.6Hz, 1H), 5.86 (s, 1H), 5.82 (s, 1H), 4.63 (m, 1H), 3.84 (m, 1H), 3.40(m, 2H), 2.81 (m, 2H), 2.43 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).

LCMS: purity: 100%. MS (m/e): 563.51 (MH⁺).

II-174:N-(3-(3,6-difluoropyridin-2-yl)-1-((cis)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 11.46 (s, 1H), 8.56 (s, 1H),8.44 (s, 1H), 8.30 (s, 1H), 8.14 (m, 2H), 7.32 (m, 1H), 4.62 (m, 1H),3.83 (m, 1H), 3.39 (m, 2H), 2.80 (m, 2H), 2.40 (m, 2H), 1.15 (t, J=7.5Hz, 3H). LCMS: purity: 100%. MS (m/e): 471.49 (MH⁺).

II-175:N-(1-((cis)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 12.07 (s, 1H), 8.65 (d, J=4.2Hz, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.85(m, 1H), 7.50 (m, 1H), 4.33 (m, 1H), 3.55 (m, 1H), 3.43 (m, 2H), 2.05(m, 2H), 1.91 (m, 4H), 1.59 (m, 2H), 1.14 (t, J=6.6 Hz, 3H).

LCMS: purity: 100%. MS (m/e): 481.55 (MH⁺).

II-176:N-(3-(3,6-difluoropyridin-2-yl)-1-((trans)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 11.47 (s, 1H), 8.53 (s, 1H),8.49 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.28 (m, 1H),4.33 (m, 1H), 3.46 (m, 1H), 3.35 (m, 2H), 2.10 (m, 2H), 1.86 (m, 4H),1.33 (m, 2H), 1.11 (t, J=7.2 Hz, 3H). LCMS: purity: 97.57%. MS (m/e):499.54 (MH⁺).

II-177:N-(3-(3,6-difluoropyridin-2-yl)-1-((cis)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (s, 1H), 11.47 (s, 1H), 8.53 (s, 1H),8.49 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.28 (m, 1H),4.36 (m, 1H), 3.55 (m, 1H), 3.43 (m, 2H), 2.05 (m, 2H), 1.90 (m, 4H),1.59 (m, 2H), 1.14 (t, J=7.2 Hz, 3H). LCMS: purity: 100%.

MS (m/e): 499.54 (MH⁺).

II-178:N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

LCMS (m/z): 455.28 (MH⁺).

II-179:N-(1-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (DMSO d₆, 300 MHz): δ 13.42 (s, 1H), 11.93 (s, 1H), 8.98 (d,J=6.7 Hz, 2H), 8.50 (s, br, 2H), 8.31 (s, IH), 8.12 (s, 1H), 0 7.50-7.47(m, 1H), 6.16-5.78 (m, 1H), 4.35-4.27 (m, 1H), 3.00-2.88 (m, 2H),2.12-1.82 (m, 6H), 1.29-1.17 (m, 2H); LCMS (m/z): 500.18 (MH⁺).

II-180:N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.49(s, OH), 8.28 (s, 1H), 8.11 (ddd, J=11.3, 9.1, 2.4 Hz, 1H), 4.31 (t,J=11.6 Hz, 1H), 3.47 (q, J=7.0 Hz, 2H), 2.08 (d, J=11.5 Hz, 4H), 1.85(q, J=12.3, 11.9 Hz, 2H), 1.35 (q, J=10.7 Hz, 2H), 1.10 (t, J=7.0 Hz,3H). LCMS (m/z): 500.44 (MH⁺).

III-1:2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide.

1H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.72(s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.98-7.88 (m, 2H),7.40-7.36 (m, 1H), 4.09 (d, J=6.9 Hz, 2H), 3.93 (s, 3H), 1.32 (m, 1H),0.59-0.53 (m, 2H), 0.45-0.40 (m, 2H); LCMS: purity: 100%; MS (m/e):390.59 (MH⁺).

III-2:2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 13.54 (s, 1H), 12.04 (s, 1H), 8.86 (ddd,J=5.0, 1.7, 0.9 Hz, 1H), 8.74 (s, 1H), 8.61-8.49 (m, 1H), 8.46 (s, 1H),8.26-8.08 (m, 1H), 8.04-7.98 (m, 1H), 7.93 (td, J=7.7, 1.8 Hz, 1H),7.44-7.34 (m, 1H), 4.67-4.42 (m, 1H), 4.06-3.95 (m, 2H), 3.55-3.42 (m,2H), 2.04 (h, J=5.0, 4.3 Hz, 4H); MS (ESI) (m/z): 406 [M+H]⁺.

III-3:N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.86 (d, J=6.7 Hz, 2H), 8.74(s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 8.01-7.90 (m, 2H), 7.42-7.38 (m,1H), 4.37 (t, J=6.7 Hz, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.46 (q, J=6.7 Hz,2H), 1.09 (t, J=6.7 Hz, 3H); LCMS (m/z): 394.21 (MH⁺).

III-4:N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.86 (d, J=6.7 Hz, 1H), 8.74(s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.06-8.03 (m, 1H), 7.97-7.92 (m,1H), 7.43-7.39 (m, 1H), 4.65-4.59 (m, 1H), 3.87-3.82 (m, 1H), 3.42 (q,J=6.7 Hz, 2H), 2.86-2.77 (m, 2H), 2.45-2.41 (m, 1H), 1.15 (t, J=6.7 Hz,3H); LCMS (m/z): 420.21 (MH⁺).

III-5:N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamideas formate salt.

LCMS (m/z): 376.20 (MH⁺).

III-6:N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-3-yl)oxazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.86 (d, J=6.7 Hz, 1H), 8.74(s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 8.01-7.90 (m, 2H), 7.42-7.38 (m,1H), 4.37 (t, J=6.7 Hz, 2H), 3.84 (t, J=6.7 Hz, 2H), 3.56-3.53 (m, 2H);3.44-3.41 (m, 2H); 3.22 (s, 3H); LCMS (m/z): 424.24 (MH⁺).

III-7:2-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

¹HNMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.87 (d, J=6.7 Hz, 1H), 8.74(s, 1H), 8.46 (s, 1H), 8.01-7.94 (m, 2H), 7.43-7.39 (m, 1H), 4.44 (t,J=6.7 Hz, 2H), 4.13-4.01 (m, 4H); LCMS (m/z): 448.17 (MH⁺).

III-8:N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (s, 1H), 12.04 (s, 1H), 8.84 (ddd,J=5.0, 1.8, 1.0 Hz, 1H), 8.71 (s, 1H), 8.46 (s, 1H), 7.98 (dt, J=8.0,1.1 Hz, 1H), 7.89 (ddd, J=8.1, 7.4, 1.8 Hz, 1H), 7.36 (ddd, J=7.4, 4.9,1.3 Hz, 1H), 6.11 (tt, J=54.9, 3.7 Hz, 1H), 4.40 (t, J=5.2 Hz, 2H), 3.96(t, J=5.3 Hz, 2H), 3.72 (td, J=15.2, 3.7 Hz, 2H).

MS (ESI) (m/z): 430 [M+H]⁺

Example 24 LPS Induced IL23p19 in THP-1 cells (with IFNγ primed) Assay

Materials and Equipment

THP-1 Cells (ATCC, Cat# TIB-202), Dimethyl Sulfoxide (DMSO)(Sigma-Aldrich, Cat# D2650), RPMI 1640 (Cellgro, Cat#10-040-CM), FetalBovine Serum (Sigma, Cat#F4135), Albumin From Bovine Serum (BSA)(Sigma-Aldrich, Cat#A7906), LPS (Serotype K-235, Sigma, Product Number L2143), IFNγ (Peprotech, Cat#300-02) Capture antibody: Human IL-23p19ELISA (e-Bioscience, Cat. #14-7238-85), Detection antibody: PrimaryMouse Biotinylated anti-human IL-12(p40/p70) (e-Bioscience, Cat.#13-7129-85), Secondary HRP-conjugated Streptavidin (R&D Systems,Cat#DY998), 1×PBST Washing Buffer (PBS-Tween tablet) (VWR International,Cat#80058-558), ELISA Blocking Buffer (PBS with 1% BSA), ELISA DilutionBuffer (PBS with 1% BSA), 384 Well Flat-Bottom, MaxiSorp Black ImmunoPlates (Thermo Scientific, Cat#12-565-346), 384 Well Flat-Bottom, WhiteTissue Culture Plates (Thermo Scientific, Cat#12-565-343), Super SignalELISA Pico Chemiluminescent Substrate (Thermo Scientific, Cat#37070),Cell Titer Glo reagent (Promega, Cat#G7573), Positive control, IKK2VIinhibitor (Calbiochem, Cat#401483), AquaMax 4000 plate washer (MolecularDevices), Luminometer, Wallac Victor2 1420 Multilabel Counter.

Method

THP-1 Cells Stimulation:

On day 1, 50K/well THP-1 cells were seeded and primed with IFNγ (50ng/mL) in 384-well plates for about 18 hours in RPMI media with 10% FBS.On day 2, the compound was serially diluted in DMSO from 5 mM in 3-folddilutions, and then diluted 1:125 in RPMI media with 10% FBS. 50 μL/well2× compound was added to 50 μL/well THP-1 cells (with IFNγ primed) induplicate in 384 well tissue culture plates. The cells werepre-incubated with compound for 1 hour at 37° C., 5% CO₂ before additionof 10 μL/well 1×LPS to give a final concentration of 1 ug/mL LPS. Day 3,after stimulation for 18 hours at 37° C., 5% CO₂, the assay plate wascentrifuged and 70 μL/well supernatant was harvested. IL-23p19 proteinin 70 μL/well of supernatant was measured by sandwich ELISA, and 25l/well Cell Titer Glo reagent was added to the remaining cells tomeasure compound toxicity.

Human IL-23p19 Sandwich ELISA:

Maxisorp immuno ELISA plates were pre-coated with 25 μL/well ofanti-IL-23p19 capture antibody (2.5 ug/mL) in PBS overnight at roomtemperature. After washing with 1×PBST, the plates were blocked using100 L/well of 1% BSA in PBS for 2 hours at room temperature. The plateswere washed three times with 1×PBST and 70 μL/well supernatant wereadded. The plates were incubated at room temperature for 2 hours withshaking and washed three times with 1×PBST. 25 μL/well of biotin labeledanti-IL-12(p40/p70) detection antibody (100 ng/mL) in PBS with 1% BSAwas added and the plates were incubated at room temperature for 2 hourswith shaking. After washing three times with 1×PBST, 25 μL/well ofstreptavidin-HRP (1:200) in PBS with 1% BSA was added and the plateswere incubated at room temperature for 20 minutes with shaking. Theplates were washed three times with 1×PBST and 25 μL/well of SuperSignal ELISA Pico Chemiluminescent Substrate were added. The plates wereread with a luminometer, and the chemiluminescence values were enteredinto Athena (Rigel) for curve fitting, EC₅₀ calculation, and databasestorage. The results are shown in Table 1.

Example 25 Compound Screening Using DC Cells

Materials

Human PBMC cells (All Cells, Cat No. PB002)

RPMI growth media containing 10% FBS

IFNγ (Peprotech, Cat No. 300-02)

GMCSF (Peprotech, Cat No. 300-03) and IL4 (Peprotech Cat No. 200-04)

White clear bottom 96 well plates (Fisher, Cat No. 07-200-587, Corning#3903)

LPS (Make 2.5 mg/ml Stock in PBS) from Sigma Aldrich (Cat No. L2018-5MG)

Cell Titer Glo reagent (Promega, Cat No. G7573)

Positive controls, IKK2VI inhibitor (Calbiochem, Cat No. 401483)

Protocol

I. Differentiation of PBMC's to DC Cells:

Human PBMC cells (400 million) obtained from the vendor were transferredinto a T-175 flask containing 15 ml RPMI media (10% FBS) and incubatefor 2 hours at 37° C. After 2 hours, the media including floating cellswas aspirated out carefully and 12 ml of fresh RPMI media (10% FBS)containing GMCSF (100 ng/ml) and IL4 (20 ng/ml) was added, and the flaskwas kept in a 37° C. incubator for 7 days.

After 3 days, fresh GMCSF (100 ng/ml) and IL4 (20 ng/ml) were added tothe flask and the incubation continued. After 7 days, the fullydifferentiated cells were harvested by spinning down (1200 rpm/5 min)and aspirating the media. The cells were suspended in fresh RPMI media(10% FBS) containing 50 ng/ml IFNγ (1000 U/ml) and then plated (50K/wellin 100 μl) onto a white clear bottom 96 well plate and left in a 37° C.incubator for 24 hours.

II. Addition of Compounds:

After 24 hours incubation, 100 μl of RPMI media was added containing 2×concentrated test compound per well to the above cell-culture media(final concentration becomes 1×) and the plates were pre-incubated for 1hour at 37° C. before stimulating with LPS.

After 1 hour compound pre-incubation, 10 μl per well of 20× concentratedLPS solution in RPMI media was added to give a final concentration of 1μg/ml. The mixture was shaken and incubated the plates at 37° C. for anadditional 18 hours.

155 μl of the supernatant was harvested from each well carefully(without the tip touching the bottom of the well) and to the remaining50 μl/well of the cell culture plate was added 50 μl of Cell Titer Gloreagent. The mixture was incubated for 1-2 minutes on a shaker and theplate was read for luminescence intensity to determine the compoundcytotoxicity. The cell culture supernatant collected above was used tocarry out IL23 ELISA (65 μl—Supernatant) and IL10 ELISA (90μl—Supernatant) as described below.

Example 26

Human IL-23 (p19/p40) ELISA Protocol (e-Biosciences)

Materials:

96-well high binding opaque white plates (from Pierce, Cat No. 15042);1×PBS; 1×TBST washing buffer;

Blocking Solution: 0.5% Casein in PBS (from BDH, Cat No. 440203H);

Dilution Solution: 1% BSA in PBS (10% BSA from Fisher, Cat No. 37525);

Capture antibody: Rat anti-human IL-23 (p19) (e-Biosciences, Cat. No.14-7238-85);

Detection antibody: Primary Mouse Biotinylated anti-human IL-12(p40/p70) (e-biosciences, Cat No. 13-7129-85);

Secondary HRP-conjugated Streptavidin (R&D Systems, Cat No. DY998);

rHuman-IL-23 (e-biosciences, Cat No. 34-8239) (Suggested startingconcentration=5 ng/ml in RPMI cell culture media);

Cell Culture Supernatant (65 μl from THP-1 cells primed with IFNγ (50ng/ml-1000 U/ml) and stimulated with 0.01% SAC);

SuperSignal ELISA Pico Chemiluminescent substrate [Pierce, Cat No.37069].

Coating Plates:

To 10.5 ml PBS add 50 μl of anti-IL23 (p19) was added capture antibody(2.5 g/ml). The mixture was mixed well and 100 μl of the coatingsolution was added to each well of the 96 well white plates from Pierce.The wells were covered and incubated overnight at 4° C.

Blocking the Plates:

The anti-IL23 (p19)-antibody-coated plates were washed 2× using TBST(use plate washer) and blocked using 200 μl of 0.5% Casein for 1.5-2hours at room temperature with shaking.

Addition of Supernatant and Detection:

The plates were washed 2× using TBST and the supernatant was transferred(65 l/well) to the above pre-blocked/IL23(p19)-antibody-coated 96 wellplate, and incubated at room temperature for 1.5 hours with shaking.

The plates were washed 4× using TBST (plate washer) and 100 l/welldetection antibody solution prepared from 2 μl of biotin labeledanti-IL-12 (p40/p70) antibody in 11 ml 1% BSA/PBS solution (1-5000dilution) was added. The plates were incubated for 1 hour with shakingat Room temperature.

Again, the plates were washed 4× with TBST and 100 μl of HRP labeledStreptavidin (R&D Systems) solution (10 μl/10 ml 1% BSA solution) wasadded, and the plates were incubated at room temperature for another 45minutes with shaking.

After 45 minutes, the plates were washed with TBST 4× and 100 ul/wellSuper Signal ELISA Pico Chemiluminescent Substrate from Pierce (3.5 mlA+3.5 ml B+3.5 ml MQ water) was added. The plates were shaken for 1-2minutes then read on a plate reader.

The EC₅₀ results from the assays described in Examples 24 and 26 areshown in Tables 1-3.

TABLE 1 IL23-p19 IL23-p19 ELISA, ELISA, Dendritic, THP1-IFNy, LPS, 10pt, LPS, 10 pt, Compound EC₅₀ (μM) EC₅₀ (μM) I-1 3.731 5.662 I-3 0.36190.4237 I-4 0.6189 0.7126 I-5 0.136 0.0826 I-6 0.9932 0.2635 I-7 0.39910.4334 I-8 0.4294 0.88 I-9 0.3092 0.281 I-10 3.271 21.94 I-11 5.1924.845 I-12 1.05 0.5925 I-13 11.01 136.5 I-14 0.5714 1.246 I-15 2.2 2.232I-16 0.4029 0.1249 I-17 0.4244 0.285 I-18 1.197 0.5139 I-19 0.3368 0.3I-20 0.1945 0.1666 I-21 0.4582 0.2013 I-22 1.552 0.2036 I-23 0.03720.0217 I-24 7777 4.218 I-25 0.0441 0.0571 I-26 0.2755 1.323 I-27 0.01580.1594 I-28 0.0218 0.0497 I-29 0.0972 0.2064 I-30 0.0589 0.038 I-311.253 6.289 I-32 0.083 0.0288 I-34 0.0144 0.0138 I-35 0.5201 0.0633 I-370.0174 0.1439 I-38 0.0582 0.1721 I-39 4.317 1.953 I-41 3.945 2.568 I-439999 4464 I-45 5.449 1.084 I-47 0.3271 0.3924 I-48 7.505 5.518 I-503.506 14.24 I-52 9999 1.378 I-54 1.575 0.617 I-55 0.8006 1.204 I-567.718 0.1562 I-58 27.53 2.812 I-60 0.0338 0.1745 I-62 0.1148 0.0481 I-640.3663 0.0777 I-65 0.1993 0.0543 I-67 0.0041 0.0723 I-69 0.3249 1.249I-70 0.0283 0.3662 I-71 0.0225 0.0265 I-72 0.005 0.0568 I-73 0.41020.697 I-74 0.1311 0.1514 I-75 0.0195 0.1024 I-77 0.041 0.0504 I-780.1051 0.0784 I-80 2.06 2.223 I-81 0.9595 0.1529 I-82 0.7802 0.2052 I-830.0932 0.0348 I-84 0.0977 0.0423 I-85 0.0196 0.0767 I-86 0.0637 0.0614I-87 0.1051 0.0433 I-89 0.0231 0.0166 I-91 0.0106 0.0122 I-93 0.0080.0108 I-95 0.0338 0.0678 I-97 0.0329 0.0362 I-99 0.0156 0.018 I-1010.0501 0.0143 I-103 0.0554 0.031 I-105 0.0265 8888 I-106 1.221 18.89I-107 0.3054 0.8602 I-108 0.7298 0.4911 I-109 0.0221 0.1041 I-110 0.38810.2792 I-111 0.0268 0.0291 I-112 0.0407 0.0428 I-133 0.3865 0.0806 I-1140.0616 0.0493 I-115 0.3649 0.0913 I-116 0.2182 0.2265 I-117 0.02570.2837 I-118 0.1607 0.0681 I-119 0.4303 0.1535 I-120 0.0948 0.0528 I-1229999 3.764 I-124 0.1012 0.0534 I-126 0.0215 0.0819 I-128 0.0604 0.1339I-130 0.023 0.0483 I-132 0.1028 0.0812 I-134 0.091 0.0296 I-136 0.08780.0448 I-138 0.6863 0.9263 I-140 0.224 0.7994 I-142 0.0262 0.0689 I-1440.0343 0.078 I-146 0.3704 0.1494 I-148 0.11 0.1732 I-150 0.2258 0.0648I-152 0.0716 0.0319 I-154 1.392 0.0575 I-156 0.1052 0.0595

TABLE 2 IL23-p19 IL23-p19 ELISA, ELISA, Dendritic, THP1-IFNy, LPS, 10pt, LPS, 10 pt, Compound EC₅₀ (μM) EC₅₀ (μM) II-1 0.7791 0.1288 II-20.2981 0.1962 II-3 0.3707 0.1976 II-4 0.3066 0.0861 II-5 0.157 0.0902II-6 6.888 0.0874 II-7 9999 6.087 II-8 9999 9999 II-10 0.0105 0.0226II-11 0.0623 0.05 II-12 0.0616 0.1353 II-13 10.39 4.799 II-14 0.00570.0434 II-15 0.0096 0.0064 II-16 0.5254 0.121 II-18 0.0314 0.3009 II-193.508 4.006 II-21 0.5689 0.3147 II-23 16.29 4.761 II-25 0.1704 0.1465II-26 0.1125 0.0771 II-27 0.3314 0.0741 II-28 0.063 0.2757 II-29 0.24820.1349 II-31 0.7993 0.1701 II-32 0.191 0.3608 II-34 0.0557 0.0861 II-350.2922 0.2064 II-36 0.2412 0.1649 II-37 0.1927 0.1293 II-38 0.77120.5055 II-39 0.1778 0.1672 II-41 0.0188 0.0413 II-43 0.0502 0.0278 II-450.1292 0.1287 II-47 3.207 1.166 II-49 0.0812 0.238 II-51 26.62 3.609II-52 7777 6.158 II-53 7777 24.07 II-54 0.1887 0.1706 II-55 0.04350.0749 II-57 0.0854 0.0418 II-58 0.112 0.1303 II-59 0.2156 0.4225 II-600.0533 0.0473 II-61 0.0504 0.0225 II-62 Not tested 6.477 II-63 5.44720.76 II-65 0.0489 0.0373 II-66 0.2438 0.1057 II-67 9999 26.22 II-689999 5011 II-69 9999 5014 II-70 1.016 1.865 II-71 10.39 49.57 II-720.1399 1.139 II-73 0.3429 0.3691 II-74 0.4046 0.4006 II-75 0.5369 2.493II-76 0.0475 0.0524 II-77 0.1457 0.1471 II-78 0.0799 0.1651 II-79 0.01520.0758 II-80 0.2467 0.0495 II-81 0.1707 0.019 II-82 0.176 0.0387 II-830.2411 0.0863 II-84 0.3039 0.085 II-85 0.2866 0.0499 II-86 5.782 0.1372II-87 Not tested 0.6147 II-88 0.3898 0.0965 II-89 1.127 0.5891 II-900.2176 0.176 II-91 9999 Not tested II-92 0.2583 Not tested II-93 99990.1087 II-94 0.0333 0.3106 II-95 6.225 2.25 II-96 0.4566 0.0837 II-979999 4183028 II-98 9999 24.64 II-99 0.9888 0.4203 II-100 0.2259 0.0561II-101 0.0355 0.023 II-102 0.0554 0.0619 II-103 9999 8.08 II-105 77775.546 II-107 2.309 1.503 II-109 0.3273 0.1399 II-111 0.0343 0.0651II-113 0.2881 0.0844 II-115 0.1593 0.0438 II-117 0.1065 0.0566 II-1180.2115 0.1086 II-120 1.17 0.6641 II-121 0.0444 0.0986 II-122 0.30370.2131 II-123 0.1489 0.0271 II-125 27.27 1.241 II-127 0.081 0.0487II-128 2.475 1.152 II-129 9999 0.377 II-130 0.0898 0.056 II-131 9.3590.3602 II-132 0.9242 0.2242 II-133 1.521 0.313 II-134 0.225 0.1021II-136 10.67 1.216 II-137 9999 0.206 II-138 9999 9999 II-139 9999 9999II-140 0.0323 0.0308 II-141 0.0517 0.2509 II-143 0.0164 0.0308 II-1450.0784 0.066 II-147 0.0987 0.0574 II-149 0.0568 0.0343 II-151 0.06220.0649 II-153 0.1411 0.7485 II-155 0.0612 0.3993 II-157 0.5641 0.0615II-158 0.0921 0.1445 II-160 0.0385 0.0267 II-161 0.4821 0.1124 II-1630.3477 0.1087 II-164 0.9118 0.1106 II-165 0.0454 0.0444 II-167 0.09620.0949 II-169 0.4098 0.042 II-170 0.0904 0.0491 II-172 0.0242 0.013II-173 0.3137 0.0414 II-174 0.0708 0.0821 II-178 0.0373 0.1193 II-1790.0748 0.0125 II-180 0.2629 0.0802

TABLE 3 IL23-p19 IL23-p19 ELISA, ELISA, Dendritic, THP1-IFNy, LPS, 10pt, LPS, 10 pt, Compound EC₅₀ (μM) EC₅₀ (μM) III-1 Not tested 20.34III-2 0.1347 0.0399 III-3 0.1704 0.2433 III-4 0.0369 0.0434 III-5 0.0710.2702 III-6 0.2171 0.2377 III-7 0.4512 0.0853 III-8 0.161 0.4003

In view of the many possible embodiments to which the principles of thedisclosed invention may be applied, it should be recognized that theillustrated embodiments are only preferred examples of the invention andshould not be taken as limiting the scope of the invention. Rather, thescope of the invention is defined by the following claims. We thereforeclaim as our invention all that comes within the scope and spirit ofthese claims.

We claim:
 1. A compound having a formula

or a pharmaceutically acceptable salt thereof, wherein: R² is aliphatic,cycloaliphatic, heteroaliphatic, or heterocycloaliphatic; each of R⁴,R⁵, R⁶, and R⁷ independently is H, aliphatic, alkoxy, halogen,—O-heterocyclyl or heterocyclic; R⁸ and R⁹ are each independently H oraliphatic; R¹⁰ is H, aliphatic, carboxyl ester, acyl, alkyl phosphate,alkyl phosphonate or aralkyl; and R¹¹ and R¹² are each independently Hor aliphatic.
 2. The compound of claim 1, wherein each of R⁴, R⁶, and R⁷independently is H, halogen, alkyl, or haloalkyl.
 3. The compound ofclaim 1, wherein each of R⁴, R⁶, and R⁷ independently is H, F or CF₃. 4.The compound of claim 1, wherein R⁵ is H, halogen, alkyl, haloalkyl,alkoxy, heterocyclyl, or —O-heterocyclyl.
 5. The compound of claim 1,wherein R⁵ is H, F, CF₃, methoxy, morpholin-4-yl,1-methylpiperidin-4-yl, —O—CH₂C(CH₃)₂OH, or —O-(oxetan-3-yl).
 6. Thecompound of claim 1, wherein R⁸ and R⁹ are each independently H,haloalkyl, or alkyl.
 7. The compound of claim 1, wherein R¹⁰ is H,alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate oraralkyl.
 8. The compound of claim 1, wherein R² is alkyl, haloalkyl, orcycloalkyl.
 9. The compound of claim 1, wherein each of R⁴, R⁵, R⁶, andR⁷ independently is H, or F.
 10. The compound of claim 9, wherein: R² isalkyl, haloalkyl, or cycloalkyl; R⁸ and R⁹ are each independently H,haloalkyl, or alkyl; and R¹⁰ is H, alkyl, alkyl phosphate, or alkylphosphonate.
 11. The compound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 14. A composition,comprising a compound of claim 1, and a pharmaceutically acceptableexcipient.
 15. The composition of claim 14, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 16. The composition ofclaim 14, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 17. The composition ofclaim 14, wherein the compound is

or a pharmaceutically acceptable salt thereof.